Aromatic compound

ABSTRACT

The compound of the present invention is represented by the following general formula (1): 
     
       
         
         
             
             
         
       
     
     [wherein X 1  represents a nitrogen atom or a group —CH═; R 1  represents a group —Z—R 6 , wherein Z represents a group —CO—, a group —CH(OH)—, or the like, and R 6  represents a 5- to 15-membered monocyclic, dicyclic, or tricyclic, saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms; R 2  represents a hydrogen atom, a halogen atom or a lower alkylene group; Y represents a group —O—, a group —CO—, a group —CH(OH)—, a lower alkylene group, or the like; and A represents a group 
     
       
         
         
             
             
         
       
     
     or the like, wherein R 3  represents a hydrogen atom, a lower alkoxy group, or the like, p represents 1 or 2, and R 4  represents an imidazolyl lower alkyl group or the like.

TECHNICAL FIELD

The present invention relates to an aromatic compound.

BACKGROUND ART

Currently, it is said that the disease known as fibrosis includes 130 types or more of diseases, if rare diseases are also included therein. Representative examples of such fibrosis include lung fibrosis, hepatic fibrosis, and glomerulosclerosis.

In general, lung fibrosis refers to a group of diseases associated with loss of lung functions due to a lesion regarding the reconstruction of an alveolar region, which is caused by the phenomenon whereby the alveoloar structure is destroyed by an inflammatory reaction, and as a result, growth of fibroblasts and an excessive increase in extracellular matrix mainly composed of collagen take place, so that the lung becomes hardened.

Moreover, hepatic fibrosis refers to a pathologic condition associated with fibrosis of the liver, which is caused by the phenomenon whereby hepatic cells are necrotized by various types of hepatopathy such as chronic viral hepatitis or alcoholic hepatitis, and thereafter, extracellular matrix increases to replenish the necrotized portion, resulting in such fibrosis of the liver. This pathologic condition finally leads to hepatic cirrhosis, in which the entire hepatic fibers shrink and become hardened.

In order to suppress the aforementioned hepatic fibrosis, drugs such as Penicillamine or Lufironil have been used. Penicillamine has been known as a drug for treating Wilkinson's disease that is developed as a result of accumulation of copper in the liver due to abnormality of copper metabolism. Lufironil has been studied for its use as a proline hydroxylase inhibitor.

However, taking into consideration their side effects and effectiveness, the aforementioned drugs do not sufficiently function as drugs for preventing fibrosis of the liver. Thus, as a matter of fact, neither therapeutic agents nor methods for treating fibrosis, which are effective for fibrosis, including hepatic fibrosis as a representative example, have been established to date. A method of specifically inhibiting a process of developing fibrosis has become a focus of attention in the research field.

As stated above, it has been known that an excessive increase in extracellular matrix mainly composed of collagen takes place during a process of development of fibrosis in the lung tissues or hepatic tissues. Moreover, it has also been known that such an increase in extracellular matrix in hepatic cells takes place mainly in sinusoidal wall Disse's space, and that Ito cells that are mesenchymal cells in the liver are main sources for production of such extracellular matrix.

Accordingly, in order to suppress fibrosis occurring in the liver, the lung, or other organs, it is important to suppress an excessive increase in extracellular matrix (namely, collagen).

JP-A-2002-507601 and JP-A-2001-89450 disclose that a certain type of pyridine derivative has an effect, of suppressing the generation of collagen and thus is effective for fibrosis. JP-A-2001-89412 discloses that a certain type of benzene derivative has an effect of suppressing the production of collagen and thus is effective for fibrosis.

However, the effect of suppressing the generation of collagen of the compounds described in JP-A-2002-507601, JP-A-2001-89450, and JP-A-2001-89412 are insufficient, or these compounds have serious side effects. Accordingly, it has strongly been desired that a compound, which has a superior effect of suppressing the production of collagen, less side effects, and excellent safety, will be developed.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide a novel compound, which has a superior effect of suppressing the generation of collagen, for example, a pharmaceutical composition being useful for preventing and treating fibrosis such as lung fibrosis, hepatic fibrosis, glomerulosclerosis and the like, with less side effects, and excellent safety.

As a result of intensive studies directed towards achieving the aforementioned object, the present inventors have found that an aromatic compound represented by the following general formula (1) and a salt thereof have a superior effect of suppressing the generation of collagen, less side effects, and excellent safety. The present invention has been completed based on these findings.

The present invention provides an aromatic compound represented by the general formula (1) or a salt thereof:

[wherein X₁ represents a nitrogen atom or a group —CH═, R¹ represents a group —Z—R⁶, Z represents a group —N(R⁸)—B—, a group —B—N(R⁸) a group —B₀—O—, a group

a group —CO—, a group —CH(OH)—, a group

a group —N═CH—, a group

a lower alkenylene group, a group —NHCO—B₁—, a group —NHCO—B₂—(W)u-, a group —B₀—O—B_(19a)—, a group

a group

a group

a group —S—, a lower alkynylene group, a lower alkylene group, a group

or a group —CO—NH—B₁₈a-, wherein R⁸ represents a hydrogen atom, a lower alkyl group that may have a lower alkoxy group as a′ substituent, a lower alkanoyl group, a phenyl lower alkyl group, or a lower alkylsulfonyl group, B represents a group —CO— or a lower alkylene group, B₀ represents a lower alkylene group, each of R^(9a) and R^(9b), which are identical or different, represents a hydrogen atom or a lower alkyl group R^(10a) represents a hydrogen atom or a lower alkyl group, B_(22a) represents a lower alkylene group or a lower alkenylene group, e represents 0 or 1, B₁ represents a lower alkenylene group that may have a phenyl group as a substituent, B₂ represents a lower alkylene group that may be substituted by a group selected from the group consisting of a lower alkoxy group and a phenyl group, W represents an oxygen atom, a group —NH—, or a sulfur atom, u represents 0 or 1, B_(18a) represents a lower alkylene group, B_(19a) represents a lower alkylene group, B_(20a) represents a lower alkylene group, B_(21a) represents a lower alkylene group, R^(8d) represents a hydrogen atom or a lower alkyl group, k represents 2 or 3, c represents 0 or 1, d′ represents 0 or 1, R^(10b) represents a hydrogen atom or a lower alkyl group, R⁶ represents a 5- to 15-membered monocyclic, dicyclic, or tricyclic saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein, the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of an oxo group; an optionally halogenated lower alkoxy group; an optionally halogenated lower alkyl group; a halogen atom; a lower alkylsulfonyl group; a phenyl group that may be substituted, on the phenyl ring, by an optionally halogenated lower alkyl group; a lower alkylthio group; a pyrrolyl group; a benzoyl group; a lower alkanoyl group; a lower alkoxycarbonyl group; and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent), an adamantyl group, a naphthyl group (wherein, the naphthalene ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a halogen atom, and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent), an alkyl group that may have a lower alkoxy group as a substituent, a cycloalkyl group that may be substituted, on the cycloalkyl ring, by a group selected from the group consisting of an amino-substituted lower alkyl group that may have a lower alkyl group on the amino group and a lower alkyl group that may have a halogen atom as a substituent, a lower alkenyl group that may have a halogen atom as a substituent, a lower alkanoyl group, a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group that may have a halogen atom as a substituent and a halogen atom, a group

a halogen atom-substituted lower alkyl group, or a cycloalkyl lower alkyl group, R⁷ represents a hydrogen atom, a phenyl group, a carboxy group, a hydroxyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a phenoxy group, a lower alkoxy group that may have a halogen atom as a substituent, a lower alkylenedioxy group, an amino group that may have, as a substituent, a group selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group, and a cycloalkyl group, a cyano group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkylsulfonyl group, an aminosulfonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein the heterocyclic ring may be substituted, by an oxo group), or a lower alkoxycarbonyl lower alkyl group, m represents an integer between 1 and 5, wherein when m represents 2 to 5, two to five Ws may be identical or different, R² represents a hydrogen atom, a halogen atom, or a lower alkyl group, Y represents a group —O—, a group —N(R⁵)—, a group —CO—, a group —CH(OH)—, a lower alkylene group, a group —S(O)n-, or a group —C(═N—OH)—, R⁵ represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a phenyl lower alkyl group, or a cycloalkyl group, n represents 0, 1, or 2, A represents a group

or a group

p represents 1 or 2, R³ represents a hydrogen atom, a lower alkoxy group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a carboxy group, a group —CONR¹¹R¹², or a cyano group, wherein each of R¹¹ and R¹², which are identical or different, represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a phenyl group, or R¹¹ and R¹², together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, R⁴ represents an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group that may have an oxo group as a substituent on the pyrimidine ring, a 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group, a 1,2,4-oxadiazolyl lower alkyl group that may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a group

a group

or a group -(T)₁-N(R¹⁴)R¹⁵, R¹³ represents a hydrogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a benzoyl group, a morpholino-substituted lower alkanoyl group, a piperazinyl carbonyl lower alkyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a morpholinocarbonyl-substituted lower alkyl group, or an imidazolyl lower alkanoyl group, R^(13a) represents a hydrogen atom or a hydroxyl group, T represents a lower alkylene group, a group —N(R¹⁷)—B₃—CO—, a group —B₉—N(R¹⁸)—CO—, a group —B₄—CO—, a group -Q-B₅—CO—, a group —B₆—N(R¹⁹)—B₇—CO—, a group —CO—B₈—, a group —CH(OH)—B₉—, a group —CO—B₁₀—CO—, a group —CH(OH)—B₁₁—CO— a group —CO—, a group —SO₂—, or a group —B_(23a)—CO—CO—, wherein R¹⁷ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylcarbonyl group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkenyl group, an amino-substituted lower alkanoyl group that may have a lower alkyl group as a substituent, or a lower alkylsulfonyl group, B₃ represents a lower alkylene group, B₁₉ represents a lower alkylene group, R¹⁸ represents a hydrogen atom or a lower alkyl group, B₄ represents a lower alkenylene group or a lower alkylene group that may have a hydroxyl group as a substituent, Q represents an oxygen atom or a group —S(O)n- (wherein n has the same meanings as described above), B₅ represents a lower alkylene group, B₆ represents a lower alkylene group, R¹⁹ represents a hydrogen atom or a lower alkanoyl group, B₇ represents a lower alkylene group, B₈ represents a lower alkylene group, B₉ represents a lower alkylene group, B₁₀ represents a lower alkylene group, B₁₁ represents a lower alkylene group, B_(23a) represents a lower alkylene group, l represents 0 or 1, R¹⁴ represents a hydrogen atom or an alkyl group that may have a hydroxyl group as a substituent, R¹⁵ represents (2) a hydroxyl group-substituted alkyl group, (3) a cycloalkyl group that may have a group selected from the group consisting of a hydroxyl group and a lower alkyl group as a substituent, (4) a phenoxy lower alkyl group, (5) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group; a lower alkoxy group that may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group that may have a lower alkyl group as a substituent; a hydroxyl group-substituted lower alkyl group; a phenyl lower alkyl group; a lower alkynyl group; an amino group that may have a lower alkylsulfonyl group as a substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; an anilino group that may have a halogen atom as a substituent on the phenyl ring; a lower alkoxycarbonyl group; a piperazinyl group that may have a lower alkyl group as a substituent on the piperazine ring; a pyrrolidinyl group that may have an oxo group as a substituent on the pyrrolidine ring; a lower alkanoylamino group; a cyano group; and a phenoxy group, (6) a phenoxy group, (7) a phenyl lower alkyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkyl group, (8) a phenyl lower alkyl group that has a lower alkylenedioxy group as a substituent on the phenyl ring, (10) a lower alkoxycarbonyl-substituted lower alkyl group, (11) a carboxy-substituted lower alkyl group, (12) an amino group that may have a lower alkanoyl group as a substituent, (13) a 1,2,3,4-tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group as a substituent(s) on the tetrahydroquinoline ring, (14) a cycloalkyl lower alkyl group, (15) a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (16) a pyridyl lower alkyl group, (17) an amino group-substituted lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, (18) a lower alkoxy lower alkyl group, (19) an imidazolyl group, (20) an imidazolyl lower alkyl group, (21) a 1,2,3,4-tetrahydroisoquinolylcarbonyl-substituted lower alkyl group, (22) a piperidinylcarbonyl group that may have a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, and a furyl lower alkyl group as a substituent on the piperidine ring, (23) a thiazolidinyl lower alkanoyl group that may have an oxo group as a substituent on the thiazolidine ring, (24) a piperidinyl group that may be substituted, on the piperidine ring, by a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, a lower alkyl group, a benzoyl group, and a furyl lower alkyl group, (25) a carbonyl lower alkyl group substituted by a group

(26) a carbonyl lower alkyl group substituted by a group

(27) a group —CO—B₂₀—N(R³⁶)R³⁷, (26a) a pyrrolidinyl lower alkyl group, (27a) a morpholino lower alkyl group, (28a) a phenyl lower alkenyl group, (29a) an anilinocarbonyl lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, (30a) an indolyl group, (31a) a piperazinyl lower alkyl group that may have, as a substituent on the piperazine ring, a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (32a) an amidino lower alkyl group that may have a lower alkyl group as a substituent, (33a) a fluorenyl group, (34a) a carbazolyl group that may have a lower alkyl group as a substituent on the carbazole ring, (35a) an amidino group that may have a lower alkyl group as a substituent, (36a) a piperazinyl-substituted oxalyl group that may have 1 to 3 groups selected from the group consisting of a phenyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group as a substituent(s) on the phenyl ring) and a pyridyl lower alkyl group as a substituent(s) on the piperazine ring, or (37a) a cyano-substituted lower alkyl group, R³⁴ represents an oxo group or a phenyl group, d represents an integer between 0 and 3, B₂₀ represents a lower alkylene group, R³⁵ and R³⁷, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring, R¹⁴ and R¹⁵, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring; or a group

wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of (28) a phenyl-substituted lower alkyl group, which has 1 to 2 phenyl groups and which may have a pyridyl group on the lower alkyl group, wherein the phenyl ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkanoyl group, an amino group that may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group, (29) a carbamoyl group, (30) a pyridyl lower alkyl group that may have, as a substituent(s) on the pyridine ring, 1 to 3 groups selected from the group consisting of a hydroxyl group and a lower alkyl group that may have a hydroxyl group as a substituent, (31) a pyrrolyl lower alkyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrrole ring, (32) a benzoxazolyl lower alkyl group, (33) a benzothiazolyl lower alkyl group, (34) a furyl lower alkyl group, (35) a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, an amino group that may have a lower alkylsulfonyl group as a substituent, a halogen atom, a lower alkoxy group, a lower alkyl group that may have a halogen atom as a substituent, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a thiazolidinylidene lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, and a lower alkylenedioxy group, (36) a pyrimidinyl group (37) a pyrazinyl group, (38) a pyridyl group, (39) a lower alkoxycarbonyl group, (40) a thiazolidinyl lower alkanoyl group that may be substituted, on the thiazolidine ring, by a group selected from the group consisting of an oxo group and a group

(wherein each of R^(a) and R^(b) represents a lower alkyl group), (41) a lower alkyl group that may have a group selected from the group consisting of a hydroxyl group and a halogen atom as a substituent, (42) a lower alkanoyl group that may have a halogen atom as a substituent, (43) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a carbamoyl group that may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group, a lower alkoxycarbonyl group, a carboxy group, a cyano group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a benzoyl group that may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group that may have a halogen atom as a substituent on the phenyl ring, and a hydroxyl group, (44) a phenyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (45) a naphthyl lower alkyl group, (46) a phenoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (47) a phenoxy lower alkyl group, (48) a phenyl lower alkoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (49) a group —(B₁₂CO)t-N(R²⁰)R²¹, (50) a group —(CO)o-B₁₃—N(R²²)R²³, (51) a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may be substituted, on the 1,2,3,4-tetrahydronaphthalene ring, by 1 to 5 lower alkyl groups as a substituent(s), (52) a cycloalkyl group that may have a hydroxyl group as a substituent, (53) a piperidinyl group that may be substituted, on the piperidine ring, by 1 to 3 lower alkyl groups as a substituent(s), (54) a quinolyl lower alkyl group, (55) a 1,2,3,4-tetrazolyl lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent on the tetrazole ring, (56) a thiazolyl lower alkyl group that may have a phenyl group as a substituent on the thiazole ring, (57) a benzoyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent(s) on the phenyl ring, (58) a piperidinyl lower alkyl group that may have a lower alkyl group as a substituent on the piperidine ring, (59) an imidazolyl group that may have 1 to 3 phenyl groups as a substituent(s) on the imidazole ring, (60) a benzimidazolyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the benzimidazole ring, (61) a pyridyl lower alkoxy group, (62) a 1,2,3,4-tetrahydroquinolyl lower alkyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (63) a 1,3,4-oxadiazolyl lower alkyl group that may have an oxo group as a substituent on the 1,3,4-oxadiazole ring, (64) a cycloalkyl lower alkyl group, (65) a tetrahydropyranyl group, (66) a thienyl lower alkyl group, (67) a pyrimidinylcarbonyl group that may have an oxo group as a substituent on the pyrimidine ring, (68) a hydroxyl group, (69) a carboxy group, (70) a lower alkoxy lower alkyl group, (71) a lower alkoxy lower alkoxy group, (72) a benzoyloxy group, (73) a lower, alkoxycarbonyl lower alkoxy group, (74) a carboxy lower alkoxy group, (75) a phenoxy lower alkanoyl group, (76) a 1,2,3,4-tetrahydroquinolylcarbonyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (77) a phenylsulfonyl group, (78) an imidazolyl lower alkanoyl group, (79) an imidazolyl lower alkyl group, (80) a pyridylcarbonyl group, (81) an imidazolylcarbonyl group, (82) a lower alkoxycarbonyl lower alkyl group, (83) a carboxy lower alkyl group, (84) a group —(O—B₁₅)s-CO—N(R²⁶)R²⁷, (85) a group —N(R²⁸)—CO—B₁₆—N(R²⁹)R³⁰, (86) a group —N(R³¹)—B₁₇—CO—N(R³²)R³³, (87) a benzoxazolyl group, (88a) a benzothienyl group, (89a) an oxo group, and (90a) a 1,2,3,4-tetrahydroquinolyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, B₁₂ represents a lower alkylene group, t represents 0 or 1, each of R²⁰ and R²¹, which are identical or different, represents a hydrogen atom; a cycloalkyl group; an amino group that may have a lower alkoxycarbonyl group as a substituent; a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring; a lower alkyl group; a lower alkyl group having 1 to 2 phenyl groups that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkylthio group; a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxy group that may have a halogen atom as a substituent and a lower alkyl group that may have a halogen atom as a substituent; a lower alkoxycarbonyl group; a cycloalkyl lower alkyl group; a pyrrolidinyl lower alkyl group that may have 1 to 3 lower alkyl groups that may have a hydroxyl group as a substituent on the pyrrolidine ring; an amino-substituted lower alkyl group that may have a group selected from the group consisting of a phenyl group and a lower alkyl group as a substituent; a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may have 1 to 5 lower alkyl groups as a substituent(s) on the 1,2,3,4-tetrahydronaphthalene ring; a naphthyl lower alkyl group; a pyridyl lower alkyl group; a quinolyl lower alkyl group; a 1,2,3,4-tetrazolyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent(s) on the tetrazole ring; a 1,2,4-triazolyl lower alkyl group; a tetrahydrofuryl lower alkyl group that may have a hydroxyl group as a substituent on the lower alkyl group; a phenoxy lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a nitro group as a substituent(s) on the phenyl ring; a phenyl lower alkanoyl group; a lower alkanoyl group that may have a halogen atom as a substituent; an imidazolyl lower alkanoyl group; a lower alkoxycarbonyl lower alkyl group; a pyridyl group; or a carboxy lower alkyl group, or R²⁰ and R²¹, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group that may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkyl group that may have a halogen atom as a substituent(s) on the phenyl ring, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, o represents 0 or 1, B₁₃ represents a lower alkylene group, each of R²² and R²³, which are identical or different, represents a hydrogen atom, a lower alkyl group, a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring, a phenoxy lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group, or a phenyl group, or R²² and R²³, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, B₁₅ represents a lower alkylene group, s represents 0 or 1, each of R²⁶ and R²⁷, which are identical or different, represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or an imidazolyl lower alkyl group, or R²⁶ and R²⁷, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring, as a substituent(s), R²⁸ represents a hydrogen atom or a lower alkyl group, B₁₆ represents a lower alkylene group, R²⁹ and R³⁰, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, R³¹ represents a hydrogen atom or a lower alkyl group, B₁₇ represents a lower alkylene group, R³² and R³³, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, provided that the above described aromatic compound or a salt thereof satisfy the following requirements (i) to (v)

-   -   (i) when X₁ represents a group —CH═, then R³ represents a         hydrogen atom;     -   (ii) when X₁ represents a group —CH—, l represents 1, T         represents —CO—, and R¹⁴ represents a hydrogen atom or an alkyl         group that may have a hydroxyl group as a substituent, then R¹⁵         represents the group (24) described above;     -   (iii) when X₁ represents a group —CH═, l represents 1, and T         represents —N(R¹⁷)—B₃—CO—, then R¹⁴ and R¹⁵, together with the         nitrogen atom to which they bind, may bind to each other,         directly or via a nitrogen atom, oxygen atom, or sulfur atom to         form a 5- to 10-membered saturated or unsaturated heterocyclic         ring, wherein the heterocyclic ring is substituted by 1 to 3         groups of (28) described above;     -   (iv) when X₁ represents a nitrogen atom, and l represents 0, or         when X₁ represents a nitrogen atom, l represents 1, and T         represents —CO— or —SO₂, then R¹⁵ is not the group being any one         of (5), (7), (19), and (20) described above; and     -   (v) when R⁶ represents a cycloalkyl group wherein the cycloalkyl         ring may be substituted by a group selected from the group         consisting of an amino-substituted lower alkyl group that may         have a lower alkyl group and a lower alkyl group that may have a         halogen atom as a substituent, then R¹⁴ represents a group         -(T)₁-N(R¹⁴)R¹⁵ (wherein T and l have the same meanings as         described above, and R¹⁴ and R¹⁵, together with the nitrogen         atom to which they bind, may bind to each other, directly or via         a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to         10-membered saturated heterocyclic ring; or R¹⁴ and R¹⁵ form a         group

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-1) to (1-7):

[wherein, in said general formulas (1-1) to (1-7), R⁶, B, R⁸, R², R⁵, n, X₁, and A have the same meanings as described above, and Y₃ represents a lower alkylene group].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-8) to (1-14):

[wherein, in said general formulas (1-8) to (1-14), R⁶, B, R⁸, R², R⁵, n, X₁, A and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-15) to (1-21):

[wherein, in said general formulas (1-15) to (1-21), R⁶, B₀, R², R⁵, n, X₁, A and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-22) to (1-28):

[wherein, in said general formulas (1-22) to (1-28), R⁶, R², R⁵, n, X₁, A and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-29) to (1-35):

[wherein, in said general formulas (1-29) to (1-35), R⁶, R², R⁵, n, X₁, A and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-36) to (1-42):

[wherein, in said general formulas (1-36) to (1-42), R⁶, R², R⁵, n, X₁, A and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-43) to (1-49):

[wherein, in said general formulas (1-43) to (1-49), R⁶, R², R⁵, n, X₁, A, R^(9a), R^(9b) and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-50) to (1-56):

[wherein, in said general formulas (1-50) to (1-56), R⁶R², R⁵, n, X₁, A and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-57) to (1-63):

[wherein, in said general formulas (1-57) to (1-63), R⁶, R², R⁶, n, X₁, A, R^(10a), B_(22a), e and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-64) to (1-70) or salts thereof:

[wherein, in said general formulas (1-64) to (1-70), R⁶, R², R⁵, n, X₁, A and Y₃ have the same meanings as described above, and Z₁ represents a lower alkenylene group].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-71) to (1-77) or salts thereof:

[wherein, in said general formulas (1-71) to (1-77), R⁶R², B₁, R⁵, n, X₁, A and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-78) to (1-84) or salts thereof:

[wherein, in said general formulas (1-78) to (1-84), R⁶, W, u, B₂, R², R⁵, n, X₁, A and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-85) to (1-91) or salts thereof:

[wherein, in said general formulas (1-85) to (1-91), R⁵, R⁶, B_(19a), B₀, R², X₁, n, A and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-92) to (1-98) or salts thereof:

[wherein, in said general formulas (1-92) to (1-98), R⁶, R⁶, B_(20a), R², X₁, A, n, d′, k and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-99) to (1-105) or salts thereof:

[wherein, in said general formulas (1-99) to (1-105), R⁶, R⁵, B_(21a), R², X₁, A, n, c and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-106) to (1-112) or salts thereof:

[wherein, in said general formulas (1-106) to (1-112), R⁵, n, R⁶, R^(10b), X₁, R², A and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-113) to (1-119) or salts thereof:

[wherein, in said general formulas (1-113) to (1-119), R⁶, R², X₁, R⁵, n, A and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-120) to (1-126) or salts thereof:

[wherein, in said general formulas (1-120) to (1-126), R⁶, R², X₁, A, R⁵, n and Y₃ have the same meanings as described above, and Z₂ represents a lower alkynylene group].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-127) to (1-133) or salts thereof:

[wherein, in said general formulas (1-127) to (1-133), R⁶, B_(18a), R², X₁, A, R⁵, n and Y₃ have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-134) to (1-140) or salts thereof:

[wherein, in said general formulas (1-134) to (1-140), R⁶, R², X₁, A, R⁵, and n have the same meanings as described in Claim 1, Y₃ has the same meanings as described in Claim 2, and Z₃ represents a lower alkylene group or a group

(R^(8d) is the same meanings as described above)].

The present invention provides the above-mentioned aromatic compound or salt thereof wherein Y is a group —O—.

The present invention provides the above-mentioned aromatic compound or salt thereof wherein Y is a group —N(R⁵)— (R⁵ has the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein Y is a group —CO—, a group —CH(OH)—, a lower alkylene group, a group —S(O)n- (n has the same meanings as described above), or a group —C(═N—OH)—.

The present invention provides the above-mentioned aromatic compound or salt thereof wherein A is a group

(R³, R⁴ and p have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein A is a group

(R⁴ has the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group that may have an oxo group as a substituent on the pyrimidine ring, a 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group, a 1,2,4-oxadiazolyl lower alkyl group that may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a group

or a group

(R¹³ and R^(13a) have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵ (T, R¹⁴ and R¹⁵ have the same meanings as described above), and l is 0.

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵ (T, R¹⁴ and R¹⁵ have the same meanings as described above), and l is 1.

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —N(R¹⁷)—B₃—CO— (R¹⁴, R¹⁵, R¹⁷ and B₃ have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —B₁₉—N(R¹⁸)—CO— (R¹⁴, R¹⁵, B₁₉ and R¹⁸ have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —B₄—CO— (R¹⁴, R¹⁵, and B₄ have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group -Q-B₅—CO— (R¹⁴, R¹⁵, Q and B₅ have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —B₆—N(R¹⁹)—B₇— (R¹⁴, R¹⁵, B₆, R¹⁹ and B₇ have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R⁵, l is 1, and T is a group —CO—B₈— (R¹⁴, R¹⁵, and B₈ have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —CH(OH)—B₉— (R¹⁴, R¹⁵, and B₉ have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —CO—B₁₀—CO— (R¹⁴, R¹⁵, and B₁₀ have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —CH(OH)—B₁₁—CO— (R¹⁴, R¹⁵, and B₁₁ have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —CO— (R¹⁴ and R¹⁵ have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —SO₂— (R¹⁴ and R¹⁵ have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group B_(23a)—CO—CO— (R¹⁴, R¹⁵ and B_(23a) have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a lower alkylene group (R¹⁴ and R¹⁵ have the same meanings as described above).

In the above-mentioned aromatic compound represented by the general formula (1) or salt thereof, the aromatic compounds represented by the general formulas (1-1), (1-2), (1-8), (1-9), (1-15), (1-16), (1-29), (1-30), (1-64) and (1-65) or salts thereof are preferable.

Further, those compounds represented by the general formulas (1-1), (1-2), (1-8), (1-9), (1-15), (1-16), (1-29), (1-30), (1-43), (1-44), (1-57), (1-58), (1-64) and (1-65) or salts thereof, wherein Y is a group —O— or a group —N(R⁵)—, A is a group

and R⁴ is a group -(T)₁-N(R¹⁴)R¹⁵ (R³, R⁴, R⁵, R¹⁴, R¹⁵, p and l have the same meanings as described above), are more preferable.

The present invention provides the aromatic compounds represented by the general formulas (1-1), (1-2), (1-8), (1-9), (1-15), (1-16), (1-29), (1-30), (1-43), (1-44), (1-57), (1-58), (1-64) and (1-65) or salts thereof, wherein

l is 1, and T is a group —N(R¹⁷)—B₃—CO— (R¹⁷ and B₃ have the same meanings as described above).

The present invention provides the aromatic compounds represented by the general formulas (1-1), (1-2), (1-8), (1-9), (1-15), (1-16), (1-29), (1-30), (1-43), (1-44), (1-57), (1-58), (1-64) and (1-65) or salts thereof, wherein

l is 1, and T is a group —B₄—CO— (B₄ have the same meanings as described above).

The present invention provides the aromatic compounds represented by the general formulas (1-1), (1-2), (1-8), (1-9), (1-15), (1-16), (1-29), (1-30), (1-43), (1-44), (1-57), (1-58), (1-64) and (1-65) or salts thereof, wherein

l is 1, and T is a group —CO—.

The present invention provides the aromatic compounds represented by the general formulas (1-1), (1-2), (1-8), (1-9), (1-15), (1-16), (1-29), (1-30), (1-43), (1-44), (1-57), (1-58), (1-64) and (1-65) or salts thereof, wherein

l is 0.

The present invention particularly provides the aromatic compounds selected from the group consisting of:

-   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide, -   N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperazin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-{6-[(4-{-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]pyridin-3-yl}-4-trifluoromethylbenzamide, -   N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide, -   N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-3,4-dichlorobenzamide, -   N-[6-({4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenyl}methylamino)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-(6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-(6-(4-{[2-[(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   1-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3-(3,4-dichlorophenyl)-1-ethylurea, -   N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-(6-{4-[3-(4-piperonylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide, -   N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-{6-[(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]pyridin-3-yl}-4-trifluoromethylbenzamide, -   N-(6-{4-[(2-{4-[4-(4-fluorobenzoyl)phenyl]-piperazin-1-yl}-2-oxoethyl)methylamino]-2-methoxyphenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide, -   2-(4-piperonylpiperazin-1-yl)-N-{3-methyl-4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenyl}-2-oxoacetamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-2-fluoro-4-trifluoromethylbenzamide, -   N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,     and -   4-(3-{3-methyl-4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]phenyl}-2-oxohexahydropyrimidin-1-yl)benzoic     acid ethyl ester, or salts thereof.

The present invention provides processes for preparing the aromatic compound represented by the general formula (1) or a salt thereof according to any one of the processes described in Reaction formulas-1 to 46, 48, 49, 52, 59, 104, 105, 108 to 132 and 135 mentioned below.

The present invention provides a pharmaceutical composition for the treatment of fibrosis, which comprises an aromatic compound represented by the general formula (1A) or a salt thereof:

[wherein X₁ represents a nitrogen atom or a group —CH═, R¹ represents a group —Z—R⁶, Z represents a group —N(R⁸)—B—, a group —B—N(R⁸)—, a group —B₀—O—, a group

a group —CO—, a group —CH(OH)—, a group

a group —N═CH—, a group

a lower alkenylene group, a group —NHCO—B₁—, a group —NHCO—B₂—(W)u-, a group —B₀—O—B_(19a)—, a group

a group

a group

a group —S—, a lower alkynylene group, a lower alkylene group, a group

or a group —CO—NH—B₁₈a-, wherein R⁸ represents a hydrogen atom, a lower alkyl group that may have a lower alkoxy group as a substituent, a lower alkanoyl group, a phenyl lower alkyl group, or a lower alkylsulfonyl group, B represents a group —CO— or a lower alkylene group, B₀ represents a lower alkylene group, each of R^(9a) and R^(9b), which are identical or different, represents a hydrogen atom or a lower alkyl group R^(10a) represents a hydrogen atom or a lower alkyl group, B_(22a) represents a lower alkylene group or a lower alkenylene group, e represents 0 or 1, B₁ represents a lower alkenylene group that may have a phenyl group as a substituent, B₂ represents a lower alkylene group that may be substituted by a group selected from the group consisting of a lower alkoxy group and a phenyl group, W represents an oxygen atom, a group —NH—, or a sulfur atom, u represents 0 or 1, B_(18a) represents a lower alkylene group, B_(19a) represents a lower alkylene group, B_(20a) represents a lower alkylene group, B_(21a) represents a lower alkylene group, R^(8d) represents a hydrogen atom or a lower alkyl group, k represents 2 or 3, c represents 0 or 1, d′ represents 0 or 1, R^(10b) represents a hydrogen atom or a lower alkyl group, R⁶ represents a 5- to 15-membered monocyclic, dicyclic, or tricyclic saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein, the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of an oxo group; an optionally halogenated lower alkoxy group; an optionally halogenated lower alkyl group; a halogen atom; a lower alkylsulfonyl group; a phenyl group that may be substituted, on the phenyl ring, by an optionally halogenated lower alkyl group; a lower alkylthio group; a pyrrolyl group; a benzoyl group; a lower alkanoyl group; a lower alkoxycarbonyl group; and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent), an adamantyl group, a naphthyl group (wherein, the naphthalene ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a halogen atom, and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent), an alkyl group that may have a lower alkoxy group as a substituent, a cycloalkyl group that may be substituted, on the cycloalkyl ring, by a group selected from the group consisting of an amino-substituted lower alkyl group that may have a lower alkyl group on the amino group and a lower alkyl group that may have a halogen atom as a substituent, a lower alkenyl group that may have a halogen atom as a substituent, a lower alkanoyl group, a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group that may have a halogen atom as a substituent and a halogen atom, a group

a halogen atom-substituted lower alkyl group, or a cycloalkyl lower alkyl group, R⁷ represents a hydrogen atom, a phenyl group, a carboxy group, a hydroxyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a phenoxy group, a lower alkoxy group that may have a halogen atom as a substituent, a lower alkylenedioxy group, an amino group that may have, as a substituent, a group selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group, and a cycloalkyl group, a cyano group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkylsulfonyl group, an aminosulfonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein the heterocyclic ring may be substituted, by an oxo group), or a lower alkoxycarbonyl lower alkyl group, m represents an integer between 1 and 5, wherein when m represents 2 to 5, two to five R^(7s) may be identical or different, R² represents a hydrogen atom, a halogen atom, or a lower alkyl group, Y represents a group —O—, a group —N(R⁵)—, a group —CO—, a group —CH(OH)—, a lower alkylene group, a group —S(O)n-, or a group —C(═N—OH)—, R⁵ represents a hydrogen atom, a lower alkyl group, a Lower alkanoyl group, a benzoyl group, a phenyl lower alkyl group, or a cycloalkyl group, n represents 0, 1, or 2, A represents a group

or a group

p represents 1 or 2, R³ represents a hydrogen atom, a lower alkoxy group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a carboxy group, a group —CONR¹¹R¹², or a cyano group, wherein each of R¹¹ and R¹², which are identical or different, represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a phenyl group, or R¹¹ and R¹², together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, R⁴ represents an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group that may have an oxo group as a substituent on the pyrimidine ring, a 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group, a 1,2,4-oxadiazolyl lower alkyl group that may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a group

a group

or a group -(T)₁-N(R¹⁴)R¹⁵, R¹³ represents a hydrogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a benzoyl group, a morpholino-substituted lower alkanoyl group, a piperazinyl carbonyl lower alkyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a morpholinocarbonyl-substituted lower alkyl group, or an imidazolyl lower alkanoyl group, R^(13a) represents a hydrogen atom or a hydroxyl group, T represents a lower alkylene group, a group —N(R¹⁷)—B₃—CO—, a group —(B₁₉)_(e)—N(R¹⁸)—CO—, a group —B₄—CO—, a group -Q-B₅—CO—, a group —B₆—N(R¹⁹)—B₇—CO—, a group —CO—B₈—, a group —CH(OH)—B₉—, a group —CO—B₁₀—CO—, a group —CH(OH)—B₁₁—CO—, a group —CO—, a group —SO₂—, or a group —B₂₃, —CO—CO—, wherein R¹⁷ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylcarbonyl group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkenyl group, an amino-substituted lower alkanoyl group that may have a lower alkyl group as a substituent, or a lower alkylsulfonyl group, B₃ represents a lower alkylene group, B₁₉ represents a lower alkylene group, e represents 0 or 1, R¹⁸ represents a hydrogen atom or a lower alkyl group, B₄ represents a lower alkenylene group or a lower alkylene group that may have a hydroxyl group as a substituent, Q represents an oxygen atom or a group —S(O)n- (wherein n has the same meanings as described above), B₅ represents a lower alkylene group, B₆ represents a lower alkylene group, R¹⁹ represents a hydrogen atom or a lower alkanoyl group, B₇ represents a lower alkylene group, B₈ represents a lower alkylene group, B₉ represents a lower alkylene group, B₁₀ represents a lower alkylene group, B₁₁ represents a lower alkylene group, B_(23a) represents a lower alkylene group, l represents 0 or 1, each of R¹⁴ and R¹⁵, which are identical or different represents (1) a hydrogen atom, (2) an alkyl group that may have a hydroxyl group as a substituent, (3) a cycloalkyl group that may have a group selected from the group consisting of a hydroxyl group and a lower alkyl group as a substituent, (4) a phenoxy lower alkyl group, (5) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group; a lower alkoxy group that may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group that may have a lower alkyl group as a substituent; a hydroxyl group-substituted lower alkyl group; a phenyl lower alkyl group; a lower alkynyl group; an amino group that may have a lower alkylsulfonyl group as substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; an anilino group that may have a halogen atom as a substituent on the phenyl ring; a lower alkoxycarbonyl group; a piperazinyl group that may have a lower alkyl group as a substituent on the piperazine ring; a pyrrolidinyl group that may have an oxo group as a substituent on the pyrrolidine ring; a lower alkanoylamino group; a cyano group; and a phenoxy group, (6) a phenoxy group, (7) a phenyl lower alkyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkyl group, (8) a phenyl lower alkyl group that has a lower alkylenedioxy group as a substituent on the phenyl ring, (9) a lower alkanoyl group, (10) a lower alkoxycarbonyl-substituted lower alkyl group, (11) a carboxy-substituted lower alkyl group, (12) an amino group that may have a lower alkanoyl group as a substituent, (13) a 1,2,3,4-tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group as a substituent(s) on the tetrahydroquinoline ring, (14) a cycloalkyl lower alkyl group, (15) a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (16) a pyridyl lower alkyl group, (17) an amino group-substituted lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, (18) a lower alkoxy lower alkyl group, (19) an imidazolyl group, (20) an imidazolyl lower alkyl group, (21) a 1,2,3,4-tetrahydroisoquinolylcarbonyl-substituted lower alkyl group, (22) a piperidinylcarbonyl group that may have a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, and a furyl lower alkyl group as a substituent on the piperidine ring, (23) a thiazolidinyl lower alkanoyl group that may have an oxo group as a substituent on the thiazolidine ring, (24) a piperidinyl group that may be substituted, on the piperidine ring, by a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, a lower alkyl group, a benzoyl group, and a furyl lower alkyl group, (25) a carbonyl lower alkyl group substituted by a group

(26) a carbonyl lower alkyl group substituted by a group

(27) a group —CO—B₂₀—N(R³⁶)R³⁷, (26a) a pyrrolidinyl lower alkyl group, (27a) a morpholino lower alkyl group, (28a) a phenyl lower alkenyl group, (29a) an anilinocarbonyl lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, (30a) an indolyl group, (31a) a piperazinyl lower alkyl group that may have, as a substituent on the piperazine ring, a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (32a) an amidino lower alkyl group that may have a lower alkyl group as a substituent, (33a) a fluorenyl group, (34a) a carbazolyl group that may have a lower alkyl group as a substituent on the carbazole ring, (35a) an amidino group that may have a lower alkyl group as a substituent, (36a) a piperazinyl-substituted oxalyl group that may have 1 to 3 groups selected from the group consisting of a phenyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group as a substituent(s) on the phenyl ring) and a pyridyl lower alkyl group as a substituent(s) on the piperazine ring, or (37a) a cyano-substituted lower alkyl group, R³⁴ represents an oxo group or a phenyl group, d represents an integer between 0 and 3, B₂₀ represents a lower alkylene group, R³⁶ and R³⁷, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring, R¹⁴ and R¹⁵, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring; or a group

wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of (28) a phenyl-substituted lower alkyl group, which has 1 to 2 phenyl groups and which may have a pyridyl group on the lower alkyl group, wherein the phenyl ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkanoyl group, an amino group that may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group, (29) a carbamoyl group, (30) a pyridyl lower alkyl group that may have, as a substituent(s) on the pyridine ring, 1 to 3 groups selected from the group consisting of a hydroxyl group and a lower alkyl group that may have a hydroxyl group as a substituent, (31) a pyrrolyl lower alkyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrrole ring, (32) a benzoxazolyl lower alkyl group, (33) a benzothiazolyl lower alkyl group, (34) a furyl lower alkyl group, (35) a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, an amino group that may have a lower alkylsulfonyl group as a substituent, a halogen atom, a lower alkoxy group, a lower alkyl group that may have a halogen atom as a substituent, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a thiazolidinylidene lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, and a lower alkylenedioxy group, (36) a pyrimidinyl group, (37) a pyrazinyl group, (38) a pyridyl group, (39) a lower alkoxycarbonyl group, (40) a thiazolidinyl lower alkanoyl group that may be substituted, on the thiazolidine ring, by a group selected from the group consisting of an oxo group and a group

(wherein each of R^(a) and R^(b) represents a lower alkyl group), (41) a lower alkyl group that may have a group selected from the group consisting of a hydroxyl group and a halogen atom as a substituent, (42) a lower alkanoyl group that may have a halogen atom as a substituent, (43) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a carbamoyl group that may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group, a lower alkoxycarbonyl group, a carboxy group, a cyano group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a benzoyl group that may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group that may have a halogen atom as a substituent on the phenyl ring, and a hydroxyl group, (44) a phenyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (45) a naphthyl lower alkyl group, (46) a phenoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (47) a phenoxy lower alkyl group, (48) a phenyl lower alkoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (49) a group —(B₁₂CO)t-N(R²⁰)R²¹, (50) a group —(CO)o-B₁₃—N(R²²)R²³, (51) a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may be substituted, on the 1,2,3,4-tetrahydronaphthalene ring, by 1 to 5 lower alkyl groups as a substituent(s), (52) a cycloalkyl group that may have a hydroxyl group as a substituent, (53) a piperidinyl group that may be substituted, on the piperidine ring, by 1 to 3 lower alkyl groups as a substituent(s), (54) a quinolyl lower alkyl group, (55) a 1,2,3,4-tetrazolyl lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent on the tetrazole ring, (56) a thiazolyl lower alkyl group that may have a phenyl group as a substituent on the thiazole ring, (57) a benzoyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent(s) on the phenyl ring, (58) a piperidinyl lower alkyl group that may have a lower alkyl group as a substituent on the piperidine ring, (59) an imidazolyl group that may have 1 to 3 phenyl groups as a substituent(s) on the imidazole ring, (60) a benzimidazolyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the benzimidazole ring, (61) a pyridyl lower alkoxy group, (62) a 1,2,3,4-tetrahydroquinolyl lower alkyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (63) a 1,3,4-oxadiazolyl lower alkyl group that may have an oxo group as a substituent on the 1,3,4-oxadiazole ring, (64) a cycloalkyl lower alkyl group, (65) a tetrahydropyranyl group, (66) a thienyl lower alkyl group, (67) a pyrimidinylcarbonyl group that may have an oxo group as a substituent on the pyrimidine ring, (68) a hydroxyl group, (69) a carboxy group, (70) a lower alkoxy lower alkyl group, (71) a lower alkoxy lower alkoxy group, (72) a benzoyloxy group, (73) a lower alkoxycarbonyl lower alkoxy group, (74) a carboxy lower alkoxy group, (75) a phenoxy lower alkanoyl group, (76) a 1,2,3,4-tetrahydroquinolylcarbonyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (77) a phenylsulfonyl group, (78) an imidazolyl lower alkanoyl group, (79) an imidazolyl lower alkyl group, (80) a pyridylcarbonyl group, (81) an imidazolylcarbonyl group, (82) a lower alkoxycarbonyl lower alkyl group, (83) a carboxy lower alkyl group, (84) a group —(O—B₁₅)s-CO—N(R²⁶)R²⁷, (85) a group —N(R²⁸)—CO—B₁₆—N(R²⁹)R³⁰, (86) a group —N(R³¹)—B₁₇—CO—N(R¹²)R³³, (87) a benzoxazolyl group, (88a) a benzothienyl group, (89a) an oxo group, and (90a) a 1,2,3,4-tetrahydroquinolyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, B₁₂ represents a lower alkylene group, t represents 0 or 1, each of R²⁰ and R²¹, which are identical or different, represents a hydrogen atom; a cycloalkyl group; an amino group that may have a lower alkoxycarbonyl group as a substituent; a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring; a lower alkyl group; a lower alkyl group having 1 to 2 phenyl groups that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkylthio group; a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxy group that may have a halogen atom as a substituent and a lower alkyl group that may have a halogen atom as a substituent; a lower alkoxycarbonyl group; a cycloalkyl lower alkyl group; a pyrrolidinyl lower alkyl group that may have 1 to 3 lower alkyl groups that may have a hydroxyl group as a substituent on the pyrrolidine ring; an amino-substituted lower alkyl group that may have a group selected from the group consisting of a phenyl group and a lower alkyl group as a substituent; a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may have 1 to 5 lower alkyl groups as a substituent(s) on the 1,2,3,4-tetrahydronaphthalene ring; a naphthyl lower alkyl group; a pyridyl lower alkyl group; a quinolyl lower alkyl group; a 1,2,3,4-tetrazolyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent(s) on the tetrazole ring; a 1,2,4-triazolyl lower alkyl group; a tetrahydrofuryl lower alkyl group that may have a hydroxyl group as a substituent on the lower alkyl group; a phenoxy lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a nitro group as a substituent(s) on the phenyl ring; a phenyl lower alkanoyl group; a lower alkanoyl group that may have a halogen atom as a substituent; an imidazolyl lower alkanoyl group; a lower alkoxycarbonyl lower alkyl group; a pyridyl group; or a carboxy lower alkyl group, or R²⁰ and R²¹, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group that may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkyl group that may have a halogen atom as a substituent(s) on the phenyl ring, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, o represents 0 or 1, B₁₃ represents a lower alkylene group, each of R²² and R²³, which are identical or different, represents a hydrogen atom, a lower alkyl group, a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring, a phenoxy lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group, or a phenyl group, or R²² and R²³, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, B₁₅ represents a lower alkylene group, s represents 0 or 1, each of R²⁶ and R²⁷, which are identical or different, represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or an imidazolyl lower alkyl group, or R²⁶ and R²⁷, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring, as a substituent(s), R²⁸ represents a hydrogen atom or a lower alkyl group, B₁₆ represents a lower alkylene group, R²⁹ and R³⁰, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, herein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, R³¹ represents a hydrogen atom or a lower alkyl group, B₁₇ represents a lower alkylene group, R³² and R³³, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring].

Further, the present invention provides the pharmaceutical composition for the treatment of fibrosis, comprising the aromatic compound represented by the general formula (1) or a salt thereof mentioned above.

The present invention provides the above-mentioned pharmaceutical composition for the treatment of fibrosis, comprising the aromatic compound or a salt thereof mentioned above, wherein the aromatic compound is selected from the group consisting of

-   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{∂2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide, -   N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperazin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-{6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]pyridin-3-yl}-4-trifluoromethylbenzamide, -   N-[6-(4-{4-[(2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide, -   N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-3,4-dichlorobenzamide, -   N-[6-({4-[3-(4-piperonylpiperazin-1-yl]-3-oxopropyl]phenyl}methylamino)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   1-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3-(3,4-dichlorophenyl)-1-ethylurea, -   N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, -   N-(6-{4-[3-(4-piperonylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide, -   N-[6-(4-{4-[(2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, -   N-{6-[(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]pyridin-3-yl}-4-trifluoromethylbenzamide, -   N-(6-{4-[(2-{4-[4-(4-fluorobenzoyl)phenyl]-piperazin-1-yl}-2-oxoethyl)methylamino]-2-methoxyphenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide, -   2-(4-piperonylpiperazin-1-yl)-N-{3-methyl-4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenyl}-2-oxoacetamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-2-fluoro-4-trifluoromethylbenzamide, -   N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,     and -   4-(3-{3-methyl-4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]phenyl}-2-oxohexahydropyrimidin-1-yl)benzoic     acid ethyl ester, or salts thereof.

The present invention provides the above-mentioned pharmaceutical composition for the treatment of fibrosis, wherein the fibrosis is lung fibrosis. The present invention provides the above-mentioned pharmaceutical composition for the treatment of fibrosis, wherein the fibrosis is hepatic fibrosis. The present invention provides the above-mentioned pharmaceutical composition for the treatment of fibrosis, wherein the fibrosis is glomerulosclerosis.

Specific examples of each group represented by the general formula (1) are as follows.

Examples of the lower alkynylene group include linear or branched alkynylene groups having 2 to 6 carbon atoms which have 2 to 6 triple bonds such as ethynylene, 1-propynylene, 1-methyl-1-propynylene, 2-methyl-1-propynylene, 2-propynylene, 2-butynylene, 1-butynylene, 3-butynylene, 2-pentynylene, 1-pentynylene, 3-pentynylene, 4-pentynylene, 2-pentyn-4-ynylene, 2-hexynylene, 1-hexynylene, 5-hexynylene, 3-hexynylene, 4-hexynylene, 3,3-diethyl-1-propynylene, 2-ethyl-1-propynylene groups.

Examples of the amino group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkanoyl group include amino groups which may have 1 or 2 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkanoyl group having 1 to 6 carbon atoms such as amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino, N-acetylamino, N-formylamino, N-propionylamino, N-butyrylamino, N-isobutyrylamino, N-pentanoylamino, N-tert-butylcarbonylamino, N-hexanoylamino, diacetylamino, N-acetyl-N-methylamino, N-acetyl-N-ethylamino groups.

Examples of the benzoyl group (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group which may have a halogen atom as a substituent and a halogen atom) include benzoyl groups (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents and a halogen atom) such as benzoyl, 3,4-difluorobenzoyl, 2-fluorobenzoyl, 3-bromobenzoyl, 4-iodobenzoyl, 4-methylbenzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 2-ethylbenzoyl, 3-ethylbenzoyl, 4-ethylbenzoyl, 4-isopropylbenzoyl, 3-butylbenzoyl, 4-pentylbenzoyl, 4-hexylbenzoyl, 3,4-dimethylbenzoyl, 3,4-diethylbenzoyl, 2,4-dimethylbenzoyl, 2,5-dimethylbenzoyl, 2,6-dimethylbenzoyl, 3,4,5-trimethylbenzoyl, 2-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl, 4-trifluoromethylbenzoyl, 2-(bromomethyl)benzoyl, 3-(2-chloroethyl)benzoyl, 4-(2,3-dichloropropyl)benzoyl, 4-(4-fluorobutyl)benzoyl, 3-(5-chloropentyl)benzoyl, 4-(5-bromohexyl)benzoyl, 4-(5,6-dibromohexyl)benzoyl, 3,4-di(trifluoromethyl)benzoyl, 3,4-di(4,4,4-trichlorobutyl)benzoyl, 2,4-di(3-chloro-2-methylpropyl)benzoyl, 2,5-di(3-chloropropyl)benzoyl, 2,6-di(2,2,2-trifluoroethyl)benzoyl, 3,4,5-tri(trifluoromethyl)benzoyl, 4-(2,2,2-trichloroethyl)benzoyl, 2-methyl-4-trifluoromethylbenzoyl, 3-ethyl-4-trichloromethylbenzoyl, 2-chloro-4-trifluoromethylbenzoyl, 3-ethyl-4-fluorobenzoyl, 3-fluoro-4-trichloromethylbenzoyl, 2-methyl-3-trifluoromethyl-4-trifluoromethylbenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2-bromobenzoyl, 4-bromobenzoyl, 2-iodobenzoyl, 3-iodobenzoyl, 2,3-dibromobenzoyl, 2,4-diiodobenzoyl, 2,5-difluorobenzoyl, 2,6-dichlorobenzoyl, 2,4,6-trichlorobenzoyl, 2,4-difluorobenzoyl, 3,5-difluorobenzoyl, 2,6-difluorobenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2,3-dichlorobenzoyl, 2,4-dichlorobenzoyl, 2,5-dichlorobenzoyl, 3,4-dichlorobenzoyl, 2,6-dichlorobenzoyl, 3,5-dichlorobenzoyl, 2,4,6-trifluorobenzoyl, 2,4-difluorobenzoyl groups.

Examples of the halogen substituted lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms which have 1 to 3 halogen atoms as substituents such as a trifluoromethyl group, trichloromethyl group, chloromethyl group, bromomethyl group, fluoromethyl group, iodomethyl group, difluoromethyl group, dibromomethyl group, dichloromethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, 3-chloropropyl group, 2,3-dichloropropyl group, 4,4,4-trichlorobutyl group, 4-fluorobutyl group, 5-chloropentyl group, 3-chloro-2-methylpropyl group, 5-bromohexyl group, and 5,6-dibromohexyl group.

Examples of the lower alkanoyl substituted amino group include linear or branched alkanoyl groups having 2 to 6 carbon atoms which have 1 to 3 halogen atoms as substituents such as a acetyl amino group, propionyl amino group, butyryl amino group, pentanoyl amino group, 2-methylpropionyl amino group and hexanoyl amino group.

Examples of the piperazinyl substituted oxalyl group which may have, on the piperazine ring, 1 to 3 substituents selected from the group consisting of a phenyl lower alkyl group (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group) and a pyridyl lower alkyl group include piperazinyl substituted oxalyl groups which may have, on the piperazine ring, 1 to 3 substituents selected from the group consisting of a phenylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms (and which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkylenedioxy group having 1 to 4 carbon atoms and a linear or branched alkoxy group having 1 to 6 carbon atoms) and a pyridylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 4-(3,4-methylenedioxybenzyl)-(1-, 2-, or 3-)piperazinyloxalyl, 4-(2-, 3-, or 4-pyridylmethyl)-(1-, 2-, or 3-)piperazinyloxalyl, 4-(3,4-dimethoxybenzyl)-(1-, 2-, or 3-)piperazinyloxalyl, 4-(2,3-methylenedioxybenzyl)-(1, 2-, or 3-)piperazinyloxalyl, 4-(3,4-ethylenedioxybenzyl)-(1-, 2-, or 3-)piperazinyloxalyl, 4-[2-(2-, 3-, or 4-pyridyl)ethyl]-(1-, 2-, or 3-)piperazinyloxalyl, 4-[3-(2-, 3-, or 4-pyridyl)propyl-(1-, 2-, or 3-)piperazinyloxalyl, 2,4-bis(2-, 3-, or 4-pyridylmethyl)-(1-, 2-, or 3-)piperazinyloxalyl, 2-(3,4-methylenedioxybenzyl)-4-(2-, 3-, or 4-pyridylmethyl)-(1-, 2-, or 3-)piperazinyloxalyl, 2,3,4-tri(2-, 3-, or 4-pyridylmethyl)-(1-, 2-, or 3-)piperazinyloxalyl groups.

Examples of the cyano substituted lower alkyl group include cyanoalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a cyanomethyl group, 2-cyanoethyl group, 1-cyanoethyl group, 3-cyanopropyl group, 4-cyanobutyl group, 5-cyanopentyl group, 6-cyanohexyl group, 1,1-dimethyl-2-cyanoethyl group, and 2-methyl-3-cyanopropyl group.

Examples of the carbamoyl group which may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group include carbamoyl groups which may have 1 or 2 groups selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms which has a linear or branched alkoxy group having 1 to 6 carbon atoms and a linear or branched alkyl group having 1 to 6 carbon atoms such as carbamoyl, N-(2-methoxyethyl)carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, dibutylcarbamoyl, dipentylcarbamoyl, dihexylcarbamoyl, N-methyl-N-ethylcarbamoyl, N-ethyl-N-propylcarbamoyl, N-methyl-N-butylcarbamoyl, N-methyl-N-hexylcarbamoyl, N-(methoxymethyl)carbamoyl, N-(3-propoxypropyl)carbamoyl, N-(4-butoxybutyl)carbamoyl, N-(4-ethoxybutyl)carbamoyl, N-(5-pentyloxypentyl)carbamoyl, N-(5-methoxypentyl)carbamoyl, N-(6-hexyloxyhexyl)carbamoyl, di(2-methoxyethyl)carbamoyl, N-(2-methoxyethyl)-N-methylcarbamoyl, N-(2-methoxyethyl)-N-ethylcarbamoyl groups.

Examples of the phenyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a halogen atom and a lower alkyl group which may have a halogen atom include phenyl groups which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a halogen atom and a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms such as phenyl, 3,4-difluorophenyl, 2-fluorophenyl, 3-bromophenyl, 4-iodophenyl, 4-methylphenyl, 2-methylphenyl, 3-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-(bromomethyl)phenyl, 3-(2-chloroethyl)phenyl, 4-(2,3-dichloropropyl)phenyl, 4-(4-fluorobutyl)phenyl, 3-(5-chloropentyl)phenyl, 4-(5-bromohexyl)phenyl, 4-(5,6-dibromohexyl)phenyl, 3,4-di(trifluoromethyl)phenyl, 3,4-di(4,4,4-trichlorobutyl)phenyl, 2,4-di(3-chloro-2-methylpropyl)phenyl, 2,5-di(3-chloropropyl)phenyl, 2,6-di(2,2,2-trifluoroethyl)phenyl, 3,4,5-tri(trifluoromethyl)phenyl, 4-(2,2,2-trichloroethyl)phenyl, 2-methyl-4-trifluoromethylphenyl, 3-ethyl-4-trichloromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-ethyl-4-fluorophenyl, 3-fluoro-4-trichloromethylphenyl, 2-methyl-3-trifluoromethyl-4-trifluoromethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 2,3-dibromophenyl, 2,4-diiodophenyl, 2,5-difluorophenyl, 2,6-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trifluorophenyl, 2,4-difluorophenyl groups.

Examples of the lower alkenylene group include linear or branched alkenylene groups having 2 to 6 carbon atoms which have 1 to 3 double bonds such as vinylene, 1-propenylene, 1-methyl-1-propenylene, 2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene, 3-butenylene, 3-pentenylene, 1-pentenylene, 2-pentenylene, 4-pentenylene, 1,3-butadienylene, 1,3-pentadienylene, 2-penten-4-ynylene, 2-hexenylene, 1-hexenylene, 5-hexenylene, 3-hexenylene, 4-hexenylene, 3,3-dimethyl-1-propenylene, 2-ethyl-1-propenylene, 1,3,5-hexatrienylene, 1,3-hexadienylene, and 1,4-hexadienylene.

Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert-butoxyl group, pentyloxy group, and hexyloxy group.

Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms such as a methyl group, ethyl group, propyl group, isopropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, butyl group, isobutyl group, tert-butyl group, isopentyl group, pentyl group, and hexyl group.

Examples of the lower alkyl group which may have a lower alkoxy group as a substituent include, in addition to the above described lower alkyl groups, linear or branched alkyl groups having 1 to 6 carbon atoms which may have a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent such as a methoxymethyl group, 1-ethoxyethyl group, 2-methoxyethyl group, 2-propoxyethyl group, 3-isopropoxypropyl group, 4-butoxybutyl group, 5-pentyloxypentyl group, 6-hexyloxyhexyl, 1,1-dimethyl-2-methoxyethyl group, 2 ethyl-3-ethoxypropyl, and 3-methoxypropyl group.

Examples of the lower alkanoyl group include alkanoyl groups having 1 to 6 carbon atoms such as a formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pentanoyl group, tert-butylcarbonyl, and hexanoyl group.

Examples of the phenyl lower alkyl group include phenylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a benzyl group, 2-phenylethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 6-phenylhexyl group, 1,1-dimethyl-2-phenylethyl group, and 2-methyl-3-phenylpropyl group.

Examples of the phenyl lower alkyl group (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group), include, in addition to the above described phenyl lower alkyl groups, phenylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms (and which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkylenedioxy group having 1 to 4 carbon atoms and a linear or branched alkoxy group having 1 to 6 carbon atoms) such as 3,4-methylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 2-(2,3-ethylenedioxyphenyl)ethyl, 1-(3,4-trimethylenedioxyphenyl)ethyl, 3-(2,3-tetramethylenedioxyphenyl)propyl, 4-(3,4-methylenedioxyphenyl)butyl, 5-(2,3-ethylenedioxyphenyl)pentyl, 6-(3,4-trimethylenedioxyphenyl)hexyl, 1,1-dimethyl-2-(2,3-methylenedioxyphenyl)ethyl, 2-methyl-3-(3,4-ethylenedioxyphenyl)propyl, 2-methoxybenzyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 4-methoxybenzyl, 1-(2-ethoxyphenyl)ethyl, 3-(3-ethoxyphenyl)propyl, 4-(4-ethoxyphenyl)butyl, 5-(4-isopropoxyphenyl)pentyl, 6-(3-butoxyphenyl)hexyl, 1,1-dimethyl-2-(4-pentyloxyphenyl)ethyl, 2-methyl-3-(4-hexyloxyphenyl)propyl, 3,4-dimethoxybenzyl, 3,4-diethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4,5-trimethoxybenzyl groups.

Examples of the lower alkylene group include linear or branched alkylene groups having 1 to 6 carbon atoms such as a methylene group, ethylene group, trimethylene group, 2-methyltrimethylene group, 2,2-dimethylethylene group, 2,2-dimethyltrimethylene group, 1-methyltrimethylene group, methylmethylene group, ethylmethylene group, tetramethylene group, pentamethylene group, and hexamethylene group.

Examples of the lower alkenylene group which may have a phenyl group as a substituent include linear or branched alkenylene groups having 2 to 6 carbon atoms which have 1 to 3 double bonds and may have a phenyl group as a substituent such as vinylene, 1-propenylene, 1-methyl-1-propenylene, 2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene, 3-butenylene, 2-pentenylene, 1-pentenylene, 3-pentenylene, 4-pentenylene, 1,3-butadienylene, 1,3-pentadienylene, 2-penten-4-ynylene, 2-hexenylene, 1-hexenylene, 5-hexenylene, 3-hexenylene, 4-hexenylene, 3,3-dimethyl-1-propenylene, 2-ethyl-1-propenylene, 1,3,5-hexatrienylene, 1,3-hexadienylene, 1,4-hexadienylene, 1-phenylvinylene, 3-phenyl-1-propenylene, 3-phenyl-1-methyl-1-propenylene, 3-phenyl-2-methyl-1-propenylene, 1-phenyl-2-propenylene, 1-phenyl-2-butenylene, 3-phenyl-1-butenylene, 1-phenyl-3-butenylene, 5-phenyl-2-pentenylene, 4-phenyl-1-pentenylene, 2-phenyl-3-pentenylene, 1-phenyl-4-pentenylene, 1-phenyl-1,3-butadienylene, 1-phenyl-1,3-pentadienylene, 1-phenyl-2-penten-4-ynylene, 1-phenyl-2-hexenylene, 3-phenyl-1-hexenylene, 4-phenyl-5-hexenylene, 6-phenyl-3-hexenylene, 5-phenyl-4-hexenylene, 1-phenyl-3,3-dimethyl-1-propenylene, 1-phenyl-2-ethyl-1-propenylene, 6-phenyl-1,3,5-hexatrienylene, 1-phenyl-1,3-hexadienylene, 2-phenyl-1,4-hexadienylene groups.

Examples of the lower alkylene group which may be substituted with a group selected from the group consisting of a lower alkoxy group and a phenyl group include, in addition to the above described lower alkylene groups, linear or branched alkylene groups having 1 to 6 carbon atoms which may be substituted with 1 or 2 groups selected from the group consisting of a linear or branched alkoxy group having 1 to 6 carbon atoms and a phenyl group such as methoxymethylene, 2-phenylethylene, 3-ethoxytriethylene, 1-propoxy-2-methyltrimethylene, 1-phenyl-2,2-dimethylethylene, 3-phenyl-2,2-dimethyltrimethylene, 2-butoxy-1-methyltrimethylene, phenylmethylmethylene, 2-pentyloxyethylmethylene, 4-phenyl-2-hexyloxytetramethylene, 3-phenylpentamethylene, 5-phenylhexamethylene, ethoxymethylene, 1-phenylethylene, 3-phenyltrimethylene, 2-phenyl-1-methoxyethylene groups.

Examples of the 5- to 15-membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocyclic group which has 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyridyl, 1,2,5,6-tetrahydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,5-triazolyl, thiazolidinyl, 1,2,3,4-tetrazolyl, thienyl, quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazyl, 2H-pyrrolyl, pyrrolyl, 1,3,4-oxadiazolyl, tetrahydropyranyl, tetrahydrofuryl, furazanyl, carbostyryl, 3,4-dihydrocarbostyryl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, indolyl, isoindolyl, indolinyl, benzoimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, carbazoyl, acridinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, imidazolyl, pyrazolidinyl, phenothiazinyl, benzofuryl, 2,3-dihydrobenzo[b]furyl, benzothienyl, phenoxatiynyl, phenoxadinyl, 4H-chromenyl, 1H-indazolyl, phenazinyl, xanthenyl, thianthrenyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, isothiazolyl, pyranyl, 2-thiazolinyl, 2-pyrazolinyl, quinuclidinyl, 1,4-benzoxadinyl, 3,4,-dihydro-2H-1,4-benzoxadinyl, 3,4-dihydro-2H-1,4-benthiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthalenyl, phenanthridinyl, 1,4-dithianaphthalenyl, dibenz[b,e]azepine, 6,11-dihydro-5H-dibenz[b,e]azepine groups.

Examples of the halogen atom include a fluorine atom, chlorine atom, bromine atom and iodine atom.

Examples of the lower alkoxy group which may have a halogen atom as a substituent include linear or branched alkoxy groups having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, 3-chloro-2-methylpropoxy, 6-bromohexyloxy, 5,6-dichlorohexyloxy groups.

Examples of the lower alkyl group which may have a halogen atom as a substituent include, in addition to the above described lower alkyl groups, linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as a trifluoromethyl group, trichloromethyl group, chloromethyl group, dichloromethyl group, bromomethyl group, fluoromethyl group, iodomethyl group, difluoromethyl group, dibromomethyl group, dichloromethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, 3-chloropropyl group, 2,3-dichloropropyl group, 4,4,4-trichlobutyl group, 4-fluorobutyl group, 5-chloropentyl group, 3-chloro-2-methylpropyl group, 5-bromohexyl group, and 5,6-dibromohexyl group.

Examples of the lower alkylsulfonyl group include linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms such as a methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, and hexylsulfonyl group.

Examples of the phenyl group which may be substituted on the phenyl ring with a lower alkyl group which may have a halogen atom include phenyl groups which may be substituted with 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms such as phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-(bromomethyl)phenyl, 3-(2-chloroethyl)phenyl, 4-(2,3-dichloropropyl)phenyl, 4-(4-fluorobutyl)phenyl, 3-(5-chloropentyl)phenyl, 4-(5-bromohexyl)phenyl, 4-(5,6-dibromohexyl)phenyl, 3,4-di(trifluoromethyl)phenyl, 3,4-di(4,4,4-trichlorobutyl)phenyl, 2,4-di(3-chloro-2-methylpropyl)phenyl, 2,5-di(3-chloropropyl)phenyl, 2,6-di(2,2,2-trifluoroethyl)phenyl, 3,4,5-tri(trifluoromethyl)phenyl, 4-(2,2,2-trichloroethyl)phenyl, 2-methyl-4-trifluoromethylphenyl, 3-ethyl-4-trichloromethyl groups.

Examples of the lower alkylthio group include linear or branched alkylthio groups having 1 to 6 carbon atoms such as a methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, tert-butylthio group, pentylthio group, and hexylthio group.

Examples of the naphthyl group which may be substituted on the naphthalene ring with 1 to 3 substituents selected from the group consisting of a lower alkyl group, a halogen atom, and an amino group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkanoyl group include naphthyl groups which may have, on the naphthalene ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, a halogen atom, and an amino group which may have 1 or 2 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkanoyl group having 1 to 6 carbon atoms such as (1- or 2-)naphthyl, 1-methyl-(2-, 3-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 2-ethyl-(1-, 3-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 3-n-propyl-(1-, 2-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 4-n-butyl-(1-, 2-, 3-, 5-, 6-, 7-, or 8-)naphthyl, 4-methyl-(1-, 2-, 3-, 5-, 6-, 7-, or 8-)naphthyl, 5-n-pentyl-(1-, 2-, 3-, 4-, 6-, 7-, or 8-)naphthyl, 6-n-hexyl-(1-, 2-, 3-, 4-, 5-, 7-, or 8-)naphthyl, 1,7-dimethyl-(2-, 3-, 4-, 5-, 6-, or 8-)naphthyl, 1,2,8-trimethyl-(3-, 4-, 5-, 6-, or 7-)naphthyl, 1-dimethylamino-(2-, 3-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 2-dimethylamino-(1-, 3-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 3-methylamino-(1-, 2-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 5-amino-(1-, 2-, 3-, 4-, 6-, 7-, or 8-)naphthyl, 5-dimethylamino-(1-, 2-, 3-, 4-, 6-, 7-, or 8-)naphthyl, 4-(N-methyl-N-ethylamino)-(1-, 2-, 3-, 5-, 6-, 7-, or 8-)naphthyl, 1-methyl-2-dimethylamino-(3-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 1-chloro-(2-, 3-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 1-acetylamino-(2-, 3-, 4-, 5-, 6-, 7-, or 8-)naphthyl groups.

Examples of the alkyl group which may have a lower alkoxy group as a substituent include, in addition to the above described alkyl groups which may have a lower alkoxy group as a substituent, linear or branched alkyl groups having 1 to 8 carbon atoms which may have a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent such as a heptyl group, 1-ethylpentyl group, octyl group, 7-methoxyheptyl group, 1-ethoxyheptyl group, 2-propoxyl-1-ethylpentyl group, 3-isopropoxyoctyl group, 7-butoxyheptyl group, 8-pentyloxyoctyl group, and 5-hexyloxy-1-ethylpentyl group.

Examples of the amino substituted lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms substituted with an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms such as aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, 2-diethylaminoethyl, 2-diisopropylaminoethyl, (N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl groups.

Examples of the cycloalkyl group include cycloalkyl groups having 3 to 16 carbon atoms such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, cycloundecyl group, cyclododecyl group, cyclotridecyl group, cycloteradecyl group, cyclopentadecyl group, and cyclohexadecyl group.

Examples of the cycloalkyl group which may be substituted with a group selected from the group consisting of an amino substituted lower alkyl group which may have a lower alkyl group and a lower alkyl group which may have a halogen as a substituent include cycloalkyl groups having 3 to 16 carbon atoms which may be substituted on the cycloalkyl ring with 1 to 3 groups selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms substituted with an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms and a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as 4-dimethylaminomethylcyclohexyl, 2-(aminomethyl)cyclopropyl, 3-(2-aminomethyl)cyclobutyl, 2-(1-aminoethyl)cyclopentyl, 3-(3-aminopropyl)cyclohexyl, 3-(4-aminobutyl)cycloheptyl, 4-(5-aminopentyl)cyclooctyl, 4-(6-aminohexyl)cyclohexyl, 2-(1,1-dimethyl-2-aminoethyl)cycloheptyl, 3-(2-methyl-3-aminopropyl)cyclopentyl, 3-(methylaminomethyl)cyclohexyl, 2-(1-ethylaminoethyl)cyclooctyl, 2-(2-propylaminoethyl)cyclohexyl, 3-(3-isopropylaminopropyl)cyclopentyl, 4-(4-butylaminobutyl)cycloheptyl, 2-(5-pentylaminopentyl)cyclohexyl, 2-(6-hexylaminohexyl)cyclopentyl, 3-(dimethylaminomethyl)cyclohexyl, 3-[(N-ethyl-N-propylamino)methyl]cycloheptyl, 4-[2-(N-methyl-N-hexylamino)ethyl]cyclooctyl, 4-dimethylaminomethylcyclononyl, 2-(aminomethyl)cyclodecyl, 3-(2-aminomethyl)cycloundecyl, 2-(1-aminoethyl)cyclododecyl, 3-(3-aminopropyl)cyclotridecyl, 3-(4-aminobutyl)cyclotetradecyl, 4-(5-aminopentyl)cyclopentadecyl, 4-(6-aminohexyl)cyclohexadecyl, 2-(1,1-dimethyl-2-aminoethyl)cyclononyl, 3-(2-methyl-3-aminopropyl)cyclodecyl, 3-(methylaminomethyl)cycloundecyl, 2-(1-ethylaminoethyl)cyclododecyl, 2-(2-propylaminoethyl)cyclotridecyl, 3-(3-isopropylaminopropyl)cyclotetradecyl, 4-(4-butylaminobutyl)cyclopentadecyl, 2-(5-pentylaminopentyl)cyclohexadecyl, 2-(6-hexylaminohexyl)cyclononyl, 3-(dimethylaminomethyl)cyclododecyl, 3-[(N-ethyl-N-propylamino)methyl]cyclodecyl, 4-[2-(N-methyl-N-hexylamino)ethyl]cyclohexadecyl, 2,2-dimethylcyclopropyl, 2-trifluoromethylcyclopropyl groups.

Examples of the lower alkenyl group include linear or branched alkenyl groups having 2 to 6 carbon atoms which have 1 to 3 double bonds such as a vinyl group, 1-propenyl group, 1-methyl-1-propenyl group, 2-methyl-1-propenyl group, 2-propenyl group, 2-butenyl group, 1-butenyl group, 3-butenyl group, 2-pentenyl group, 1-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1,3-butadienyl group, 1,3-pentadienyl group, 2-penten-4-ynyl group, 2-hexenyl group, 1-hexenyl group, 5-hexenyl group, 3-hexenyl group, 4-hexenyl group, 3,3-dimethyl-1-propenyl group, 2-ethyl-1-propenyl group, 1,3,5-hexatrienyl group, 1,3-hexadienyl group, and 1,4-hexadienyl group.

Examples of the lower alkenyl group which may have a halogen atom as a substituent include, in addition to the above described lower alkenyl groups, linear or branched alkenyl groups having 2 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents and 1 to 3 double bonds such as 3,3,3-trifluoro-1-propenyl, 2-bromovinyl, 3-chloro-1-propenyl, 3-iodo-1-methyl-1-propenyl, 3-fluoro-2-methyl-1-propenyl, 2-butenyl, 4,4,3-trichloro-1-butenyl, 4,4-difluoro-3-butenyl, 5-fluoro-2-pentenyl, 5,5,3-tribromo-1-pentenyl, 5-chloro-3-pentenyl, 5,5,5-trifluoro-4-pentenyl, 4-chloro-1,3-butadienyl, 5-fluoro-1,3-pentadienyl, 5-bromo-2-penten-4-ynyl, 6-fluoro-2-hexenyl, 6,6,5-trifluoro-1-hexenyl, 6-chloro-5-hexenyl, 5-bromo-3-hexenyl, 6-chloro-4-hexenyl, 3,3-dimethyl-2-chloro-1-propenyl, 3-fluoro-2-ethyl-1-propenyl, 6-chloro-1,3,5-hexatrienyl, 6-bromo-1,3-hexadienyl, 6-fluoro-1,4-hexadienyl groups.

Examples of the lower alkylenedioxy group include linear or branched alkylene groups having 1 to 4 carbon atoms such as a methylenedioxy group, ethylenedioxy group, trimethylenedioxy group, and tetramethylenedioxy group.

Examples of the amino group which may have a substituent selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group and a cycloalkyl group include amino groups which may have 1 or 2 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkanoyl group having 1 to 6 carbon atoms, a benzoyl group, and a cycloalkyl group having 3 to 16 carbon atoms such as amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino, N-methyl-N-acetylamino, N-acetylamino, N-formylamino, N-propionylamino, N-butyrylamino, N-isobutyrylamino, N-pentanoylamino, N-tert-butylcarbonylamino, N-hexanoylamino, N-ethyl-N-acetylamino, N-benzoylamino, N-ethyl-N-benzoylamino, N-methyl-N-benzoylamino, N-acetyl-N-benzoylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, N-methyl-N-cyclohexylamino, N-methyl-N-cyclopentylamino, N-methyl-N-cycloheptylamino, N-cyclohexyl-N-acetylamino, N-cyclopentyl-N-benzoylamino, cyclononylamino, cyclodecylamino, cyclododecylamino, cyclotridecylamino, cyclotetradecylamino, cyclopentadecylamino, N-methyl-N-cyclohexadecylamino, N-methyl-N-cyclononylamino, N-methyl-N-cyclodecylamino, N-cycloundecyl-N-acetylamino, N-cyclohexadecyl-N-benzoylamino groups.

Examples of the lower alkanoyl group which may have a halogen atom as a substituent include, in addition to the above described lower alkanoyl groups, linear or branched alkanoyl groups having 2-6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as a 2,2,2-trifluoroacetyl group, 2,2,2-trichloroacetyl group, 2-chloroacetyl group, 2-bromoacetyl group, 2-fluoroacetyl group, 2-iodoacetyl group, 2,2-difluoroacetyl group, 2,2-dibromoacetyl group, 3,3,3-trifluoropropionyl group, 3,3,3-trichloropropionyl group, 3-chloropropionyl group, 2,3-dichloropropionyl group, 4,4,4-trichlorobutyryl group, 4-fluorobutyryl group, 5-chloropentanoyl group, 3-chloro-2-methylpropionyl group, 6-bromohexanoyl group, and 5,6-dibromohexanoyl group.

Examples of the lower alkoxycarbonyl group include linear or branched alkoxycarbonyl groups having 1 to 6 carbon atoms such as a methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, and hexyloxycarbonyl group.

Examples of the lower alkanoyloxy group include linear or branched alkanoyloxy groups having 2 to 6 carbon atoms such as an acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, pentanoyloxy group, tert-butylcarbonyloxy group, and hexanoyloxy group.

Examples of the 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, pyridyl, 1,2,5,6-tetrahydropyridyl, thienyl, pyrazyl, pyrimidyl, pyridazyl, pyrrolyl, 2H-pyrrolyl, imidazolidinyl, pyrazolyl, imidazolyl, pyrazolidinyl, furazanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, pyranyl, 2-pyrazolidinyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,5-triazolyl, thiazolidinyl, 2-thiazolinyl, 1,2,3,4-tetrazolyl, 1,3,4-oxadiazolyl, tetrahydropyranyl, tetrahydrofuryl groups.

Examples of the 5- to 7-membered saturated heterocyclic ring formed by binding R¹ and R¹² each other, together with nitrogen atoms bound to them, through or not through a nitrogen atom, a sulfur atom or an oxygen atom, include a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, thiomorpholino group, and homopiperazinyl group.

Examples of the imidazolyl lower alkyl group include imidazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (1, 2, 4 or 5-)imidazolylmethyl group, 2-[(1, 2, 4 or 5-)imidazolyl]ethyl group, 1-[(1, 2, 4 or 5-)imidazolyl]ethyl group, 3-[(1, 2, 4 or 5-)imidazolyl]propyl group, 4-[(1, 2, 4 or 5-)imidazolyl]butyl group, 5-[(1, 2, 4 or 5-)imidazolyl]pentyl group, 6-[(1, 2, 4 or 5-)imidazolyl]hexyl group, 1,1-dimethyl-[(1, 2, 4 or 5-)imidazolyl]ethyl group, and 2-methyl-3-[(1, 2, 4 or 5-)imidazolyl]propyl group.

Examples of the 1,2,4-triazolyl lower alkyl group include 1,2,4-triazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 3, or 5-)1,2,4-triazolylmethyl, 2-[(1, 3, or 5-)1,2,4-triazolyl]ethyl, 1-[(1, 3, or 5-)1,2,4-triazolyl]ethyl, 3-[(1, 3, or 5-)1,2,4-triazolyl]propyl, 4-[(1, 3, or 5-)1,2,4-triazolyl]butyl, 5-[(1, 3, or 5-)1,2,4-triazolyl]pentyl, 6-[(1, 3, or 5-)1,2,4-triazolyl]hexyl, 1,1-dimethyl-2-[(1, 3, or 5-)1,2,4-triazolyl]ethyl, 2-methyl-3-[(1, 3, or 5-)1,2,4-triazolyl]propyl groups.

Examples of the 1,2,3-triazolyl lower alkyl group include 1,2,3-triazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 4, or 5-)1,2,3-triazolylmethyl, 2-[(1, 4, or 5-)1,2,3-triazolyl]ethyl, 1-[(1, 4, or 5-)1,2,3-triazolyl]ethyl, 3-[(1, 4, or 5-)1,2,3-triazolyl]propyl, 4-[(1, 4, or 5-)1,2,3-triazolyl]butyl, 5-[(1, 4, or 5-)1,2,3-triazolyl]pentyl, 6-[(1, 4, or 5-)1,2,3-triazolyl]hexyl, 1,1-dimethyl-2-[(1, 4, or 5-)1,2,3-triazolyl]ethyl, 2-methyl-3-[(1, 4, or 5-)1,2,3-triazolyl]propyl groups.

Examples of the 1,2,5-triazolyl lower alkyl group include 1,2,5-triazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 3, or 4-)1,2,5-triazolylmethyl, 2-[(1, 3, or 4-)1,2,5-triazolyl]ethyl, 1-[(1, 3, or 4-)1,2,5-triazolyl]ethyl, 3-[(1, 3, or 4-)1,2,5-triazolyl]propyl, 4-[(1, 3, or 4-)1,2,5-triazolyl]butyl, 5-[(1, 3, or 4-)1,2,5-triazolyl]pentyl, 6-[(1, 3, or 4-)1,2,5-triazolyl]hexyl, 1,1-dimethyl-2-[(1, 3, or 4-)1,2,5-triazolyl]ethyl, 2-methyl-3-[(1, 3, or 4-)1,2,5-triazolyl]propyl groups.

Examples of the pyrazolyl lower alkyl group include pyrazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (1, 3, 4 or 5-)pyrazolylmethyl group, 2-[(1, 3, 4 or 5-)1,2,5-pyrazolyl]ethyl group, 1-[(1, 3, 4 or 5-)pyrazolyl]ethyl group, 3-[(1, 3, 4 or 5-)pyrazolyl]propyl group, 4-[(1, 3, 4 or 5-)pyrazolyl]butyl group, 5-[(1, 3, 4 or 5-)pyrazolyl]pentyl group, 6-[(1, 3, 4 or 5-)pyrazolyl]hexyl group, 1,1-dimethyl-2-[(1, 3, 4 or 5-)pyrazolyl]ethyl group, and 2-methyl-3-[(1, 3, 4 or 5-)pyrazolyl]propyl group.

Examples of the pyrimidinyl lower alkyl group include pyrimidinylalkyl groups which may have 1 to 3 oxo groups as substituents on the pyrimidine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 4, 5, or 6-)pyrimidinylmethyl, 2-[(2, 4, 5, or 6-)pyrimidinyl]ethyl, 1-[(2, 4, 5, or 6-)pyrimidinyl]ethyl, 3-[(2, 4, 5, or 6-)pyrimidinyl]propyl, 4-[(2, 4, 5, or 6-)pyrimidinyl]butyl, 5-[(2, 4, 5, or 6-)pyrimidinyl]pentyl, 6-[(2, 4, 5, or 6-)pyrimidinyl]hexyl, 1,1-dimethyl-2-[(2, 4, 5, or 6-)pyrimidinyl]ethyl, 2-methyl-3-[(2, 4, 5, or 6-)pyrimidinyl]propyl, [(1, 3, 4, or 5-)2,6-dioxopyrimidinyl]methyl, [(1, 3, 4, 5, or 6-)-2-oxopyrimidinyl]methyl, [(1, 2, 4, or 5-)6-oxopyrimidinyl]methyl, [(1, 2, 5, or 6-)4-oxopyrimidinyl]methyl, [(1, 3, 5, or 6-)2,4-dioxopyrimidinyl]methyl, 2-[(4 or 6-)2,5-dioxopyrimidinyl]ethyl, 1-[(1, 3, 4, or 5-)2,6-dioxopyrimidinyl]ethyl, 3-[(1,3,5-)2,4,6-trioxopyrimidinyl]propyl, 4-[(1, 3, 4, or 5-)2,6-dioxopyrimidinyl]butyl, 5-[(4 or 6-)2,5-dioxopyrimidinyl]pentyl, 6-[(1, 3, 5, or 6-)2,4-dioxopyrimidinyl]hexyl, 1,1-dimethyl-2-[(1, 3, 4, or 5-)2,6-dioxopyrimidinyl]ethyl, 2-methyl-3-[(1, 3, 4, or 5-)2,6-dioxopyrimidinyl]propyl groups.

Examples of the 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group include 3,5-dioxoisoxazolidin-4-ylidenealkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a 3,5-dioxoisoxazolidin-4-ylidenemethyl group, 3,5-dioxoisoxazolidin-4-ylideneethyl group, 3,5-dioxoisoxazolidin-4-ylidenepropyl group, 3,5-dioxoisoxazolidin-4-ylideneisopropyl group, 3,5-dioxoisoxazolidin-4-ylidenebutyl group, 3,5-dioxoisoxazolidin-4-ylidenepentyl group, and 3,5-dioxoisoxazolidin-4-ylidenehexyl group.

Examples of the 1,2,4-oxadiazolyl lower alkyl group which may have a lower alkyl group as a substituent on the 1,2,4-oxadiazol ring include 1,2,4-oxadiazolylalkyl groups which may have a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the 1,2,4-oxadiazol ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (3 or 5-)1,2,4-oxadiazolylmethyl, 2-[(3 or 5-)1,2,4-oxadiazolyl]ethyl, 1-[(3 or 5-)1,2,4-oxadiazolyl]ethyl, 3-[(3 or 5-)1,2,4-oxadiazolyl]propyl, 4-[(3 or 5-)1,2,4-oxadiazolyl]butyl, 5-[(3 or 5-)1,2,4-oxadiazolyl]pentyl, 6-[(3 or 5-)1,2,4-oxadiazolyl]hexyl, 1,1-dimethyl-2-[(3 or 5-)1,2,4-oxadiazolyl]ethyl, 2-methyl-3-[(3 or 5-)1,2,4-oxadiazolyl]propyl, 5-methyl-3-(1,2,4-oxadiazolyl]methyl, 3-ethyl-2-[(5-(1,2,4-oxadiazolyl)]ethyl, 1-[3-propyl-5-(1,2,4-oxadiazolyl)]ethyl, 3-[5-butyl-3-(1,2,4-oxadiazolyl)]propyl, 4-[3-pentyl-5-(1,2,4-oxadiazolyl)]butyl, 5-[5-hexyl-3-(1,2,4-oxadiazolyl)]pentyl, 6-[3-methyl-5-(1,2,4-oxadiazolyl)]hexyl, 1,1-dimethyl-2-[(5-isopropyl-3-(1,2,4-oxadiazolyl)]ethyl, 2-methyl-3-[3-isobutyl-5-(1,2,4-oxadiazolyl)]propyl groups.

Examples of the thiazolydinyl lower alkyl group which may have an oxo group as a substituent on the thiazolydine ring include thiazolydinylalkyl groups which may have 1 to 3 oxo groups as substituents on the thiazolydine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 3, 4, or 5-)thiazolidinylmethyl, 2-[(2, 3, 4, or 5-)thiazolidinyl]ethyl, 1-[(2, 3, 4, or 5-)thiazolidinyl]ethyl, 3-[(2, 3, 4, or 5-)thiazolidinyl]propyl, 4-[(2, 3, 4, or 5-)thiazolidinyl]butyl, 5-[(2, 3, 4, or 5-)thiazolidinyl]pentyl, 6-[(2, 3, 4, or 5-)thiazolidinyl]hexyl, 1,1-dimethyl-2-[(2, 3, 4, or 5-)thiazolidinyl]ethyl, 2-methyl-3-[(2, 3, 4, or 5-)thiazolidinyl]propyl, 2,4-dioxo-5-thiazolidinylmethyl, 2-[2-oxo-(3, 4, or 5-)thiazolidinyl]ethyl, 1-[(4-oxo-(2, 3, or 5-)thiazolidinyl]ethyl, 3-[5-oxo-(2, 3, or 4-)thiazolidinyl]propyl, 4-[2,5-dioxo-(3 or 4-)thiazolidinyl]butyl, 5-[2,4,5-trioxo-3-thiazolidinyl]pentyl, 6-[4,5-dioxo-(2 or 3-)thiazolidinyl]hexyl, 1,1-dimethyl-2-[2,4-dioxo-(3 or 5-)thiazolidinyl]ethyl, 2-methyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propyl, 3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propyl groups.

Examples of the phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring include, in addition to the above described phenyl lower alkyl groups, phenylalkyl groups which may have a linear or branched alkylenedioxy group as a substituent on the phenyl ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 3,4-methylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 2-(2,3-ethylenedioxyphenyl)ethyl, 1-(3,4-trimethylenedioxyphenyl)ethyl, 3-(2,3-tetramethylenedioxyphenyl)propyl, 4-(3,4-methylenedioxyphenyl)butyl, 5-(2,3-ethylenedioxyphenyl)pentyl, 6-(3,4-trimethylenedioxyphenyl)hexyl, 1,1-dimethyl-2-(2,3-methylenedioxyphenyl)ethyl, 2-methyl-3-(3,4-ethylenedioxyphenyl)propyl groups.

Examples of the lower alkoxycarbonyl lower alkyl group include alkoxycarbonylalkyl groups of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms and the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a methoxycarbonylmethyl group, ethoxycarbonylmethyl group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylmethyl group, 1-ethoxycarbonylethyl group, 3-methoxycarbonylpropyl group, 3-ethoxycarbonylpropyl group, 4-ethoxycarbonylbutyl group, 5-isopropoxycarbonylpentyl group, 6-propoxycarbonylhexyl group, 1,1-dimethyl-2-butoxycarbonylethyl group, 2-methyl-3-tert-butoxycarbonylpropyl-group, 2-pentyloxycarbonylethyl group, and hexyloxycarbonylmethyl group.

Examples of the carboxy lower alkyl group include carboxyalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a carboxymethyl group, 2-carboxyethyl group, 1-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group, 5-carboxypentyl group, 6-carboxyhexyl group, 1,1-dimethyl-2-carboxyethyl group, and 2-methyl-3-carboxypropyl group.

Examples of the morpholino substituted lower alkanoyl group include morpholino substituted alkanoyl groups of which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as a 2-[(2, 3 or 4-)morpholino]acetyl group, 3-[(2, 3 or 4-)morpholino]propionyl group, 2-[(2, 3 or 4-)morpholino]propionyl group, 4-[(2, 3 or 4-)morpholino]butyryl group, 5-[(2, 3 or 4-)morpholino]pentanoyl group, 6-[(2, 3 or 4-)morpholino]hexanoyl group, 2,2-dimethyl-2-[(2, 3 or 4-)morpholino]propionyl group, and 2-methyl-3-[(2, 3 or 4-)morpholino]propionyl group.

Examples of the piperazinylcarbonyl lower alkyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring include piperazinylcarbonylalkyl groups which may be substituted on the piperazine ring with 1 to 3 phenylalkyl groups which may have a linear or branched alkylenedioxy group having 1 to 4 carbon atoms and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, the piperazinylcarbonylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as [(1, 2, or 3-)piperazinyl]carbonylmethyl, 2-[(1, 2, or 3-)piperazinyl]carbonylethyl, 1-[(1, 2, or 3-)piperazinyl]carbonylethyl, 3-[(1, 2, or 3-)piperazinyl]carbonylpropyl, 4-[(1, 2, or 3-)piperazinyl]carbonylbutyl, 5-[(1, 2, or 3-)piperazinyl]carbonylpentyl, 6-[(1, 2, or 3-)piperazinyl]carbonylhexyl, 1,1-dimethyl-2-[(1, 2, or 3-)piperazinyl]carbonylethyl, 2-methyl-3-[(1, 2, or 3-)piperazinyl]carbonylpropyl, (4-benzyl-1-piperazinylcarbonyl)methyl, 2-[4-(2-phenylethyl)-1-piperazinylcarbonyl]ethyl, 1-[4-(3-phenylpropyl)-1-piperazinylcarbonyl]ethyl, 3-[4-(4-phenylbutyl)-1-piperazinylcarbonyl]propyl, 4-[4-(5-phenylpentyl)-1-piperazinylcarbonyl]butyl, 5-[4-(6-phenylpropyl)-1-piperazinylcarbonyl]pentyl, 6-(4-benzyl-1-piperazinylcarbonyl)hexyl, 1,1-dimethyl-2-(4-benzyl-1-piperazinylcarbonyl)ethyl, 2-methyl-3-(4-benzyl-1-piperazinylcarbonyl)propyl, [4-(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]methyl, 2-{4-[2-(2,3-ethylenedioxyphenyl)ethyl]-1-piperazinylcarbonyl}ethyl, 1-{4-[3-(3,4-trimethylenedioxyphenyl)propyl]-1-piperazinylcarbonyl}ethyl, 3-{4-[4-(2,3-tetramethylenedioxyphenyl)butyl]-1-piperazinylcarbonyl}propyl, 4-{4-[5-(3,4-methylenedioxyphenyl)pentyl]-1-piperazinylcarbonyl}butyl, 5-{4-[3-(2,3-ethylenedioxyphenyl)propyl]-1-piperazinylcarbonyl}pentyl, 6-[4-(3,4-trimethylenedioxybenzyl)-1-piperazinylcarbonyl]hexyl, 1,1-dimethyl-2-[4-(2,3-tetramethylenedioxybenzyl)-1-piperazinylcarbonyl]ethyl, 2-methyl-3-[4-(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]propyl, (3,4-dibenzyl-1-piperazinylcarbonyl)methyl, (3,4,5-tribenzyl-1-piperazinylcarbonyl)methyl, [2,4-di(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl])methyl, [2,4,6-tri(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]methyl, [3-benzyl-4-(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]methyl groups.

Examples of the piperazinyl lower alkanoyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring include piperazinylalkanoyl groups which may be substituted on the piperazine ring with 1 to 3 phenylalkyl groups which may have a linear or branched alkylenedioxy group having 1 to 4 carbon atoms as a substituent on the phenyl ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, the piperazinylalkanoyl groups of which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms, such as 2-[(1, 2, or 3-)piperazinyl]acetyl, 3-[(1, 2, or 3-)piperazinyl]propionyl, 2-[(1, 2, or 3-)piperazinyl]propionyl, 4-[(1, 2, or 3-)piperazinyl]butyryl, 5-[(1, 2, or 3-)piperazinyl]pentanoyl, 6-[(1, 2, or 3-)piperazinyl]hexanoyl, 2,2-dimethyl-3-[(1, 2, or 3-)piperazinyl]propionyl, 2-methyl-3-[(1, 2, or 3-)piperazinyl]propionyl, 2-(4-benzyl-1-piperazinyl]acetyl, 3-[4-(2-phenylethyl)-1-piperazinyl]propionyl, 2-[4-(3-phenylpropyl)-1-piperazinyl]propionyl, 4-[4-(4-phenylbutyl)-1-piperazinyl]butyryl, 5-[4-(5-phenylpentyl)-1-piperazinyl]pentanoyl, 6-[4-(6-phenylpropyl)-1-piperazinyl]hexanoyl, 6-(4-benzyl-1-piperazinyl)hexanoyl, 2,2-dimethyl-3-(4-benzyl-1-piperazinyl)propionyl, 2-methyl-3-(4-benzyl-1-piperazinyl)propionyl, 2-[(4-(3,4-methylenedioxybenzyl)-1-piperazinyl])acetyl, 3-{4-[2-(2,3-ethylenedioxyphenyl)ethyl]-1-piperazinyl}propionyl, 2-{4-[(3-(3,4-trimethylenedioxyphenyl)propyl]-1-piperazinyl}propionyl, 4-{4-[4-(2,3-tetramethylenedioxyphenyl)butyl]-1-piperazinyl}butyryl, 5-{4-[5-(3,4-methylenedioxyphenyl)pentyl]-1-piperazinyl}pentanoyl, 5-{4-[3-(2,3-ethylenedioxyphenyl)propyl]-1-piperazinyl}pentanoyl, 6-(4-(3,4-trimethylenedioxybenzyl)-1-piperazinyl])hexanoyl, 2,2-dimethyl-3-[(4-(2,3-tetramethylenedioxybenzyl)-1-piperazinyl]propionyl, 2-methyl-3-[4-(3,4-methylenedioxybenzyl)-1-piperazinyl]propionyl, 2-(3,4-dibenzyl-1-piperazinyl)acetyl, 2-(3,4,5-tribenzyl-1-piperazinyl)acetyl, 2-[2,4-di(3,4-methylenedioxybenzyl)-1-piperazinyl])acetyl, 2-[2,4,6-tri(3,4-methylenedioxybenzyl)-1-piperazinyl])acetyl, 2-[3-benzyl-4-(3,4-methylenedioxybenzyl)-1-piperazinyl])acetyl groups.

Examples of the morpholinocarbonyl substituted lower alkyl group include morpholinocarbonylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2, 3, or 4-)morpholino]carbonylmethyl, 2-[(2, 3, or 4-)morpholino]carbonylethyl, 1-[(2, 3, or 4-)morpholino]carbonylethyl, 3-[(2, 3, or 4-)morpholino]carbonylpropyl, 4-[(2, 3, or 4-)morpholino]carbonylbutyl, 5-[(2, 3, or 4-)morpholino]carbonylpentyl, 6-[(2, 3, or 4-)morpholino]carbonylhexyl, 1,1-dimethyl-2-[(2, 3, or 4-)morpholino]carbonylethyl, 2-methyl-3-[(2, 3, or 4-)morpholino]carbonylpropyl groups.

Examples of the imidazolyl lower alkanoyl group include imidazolylalkanoyl groups of which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as a 2-[(1, 2, 4 or 5-)imidazolyl]acetyl group, 3-[(1, 2, 4 or 5-)imidazolyl]propionyl group, 2-[(1, 2, 4 or 5-)imidazolyl]propionyl group, 4-[(1, 2, 4 or 5-)imidazolyl]butyryl group, 5-[(1, 2, 4 or 5-)imidazolyl]pentanoyl group, 6-[(1, 2, 4 or 5-)imidazolyl]hexanoyl group, 2,2-dimethyl-3-[(1, 2, 4 or 5-)imidazolyl]propionyl group, and 2-methyl-3-[(1,2,4 or 5-)imidazolyl]propionyl group.

Examples of the cycloalkylcarbonyl group include cycloalkylcarbonyl groups of which the cycloalkyl moiety is a cycloalkyl group having 3 to 16 carbon atoms such as a cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, cyclohexylcarbonyl group, cycloheptylcarbonyl group, cyclooctylcarbonyl group, cyclononylcarbonyl group, cyclodecylcarbonyl group, cycloundecylcarbonyl group, cyclododecylcarbonyl group, cyclotridecylcarbonyl group, cyclotetradecylcarbonyl group, cyclopentadecylcarbonyl group, and cyclohexadecylcarbonyl group.

Examples of the amino substituted lower alkanoyl group which may have a lower alkyl group as a substituent include linear or branched alkanoyl groups having 2 to 6 carbon atoms substituted with an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents such as aminoacetyl, 2-aminopropionyl, 3-aminopropionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 2,2-dimethyl-3-aminopropionyl, 2-methyl-3-aminopropionyl, methylaminoacetyl, 2-ethylaminopropionyl, 3-propylaminopropionyl, 3-isopropylaminopropionyl, 4-butylaminobutyryl, 5-pentylaminopentanoyl, 6-hexylaminohexanoyl, dimethylaminoacetyl, 3-diisopropylaminopropionyl, (N-ethyl-N-propylamino)acetyl, 2-(N-methyl-N-hexylamino)acetyl groups.

Examples of the lower alkylene group which may have a hydroxyl group as a substituent include, in addition to the above described lower alkylene groups, linear or branched alkylene groups having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as substituents such as 1-hydroxymethylene, 2-hydroxyethylene, 1-hydroxyethylene, 2-hydroxytrimethylene, 3-hydroxytrimethylene, 1-hydroxytrimethylene, 3-hydroxy-2-methyltrimethylene, 1-hydroxy-2-methyltrimethylene, 3-hydroxy-2,2-dimethyltrimethylene, 1-hydroxy-2,2-dimethyltrimethylene, 3-hydroxy-1-methyltrimethylene, 2-hydroxy-1-methyltrimethylene, 1-hydroxymethylmethylene, hydroxymethylmethylene, 2-hydroxymethyltrimethylene, 2-hydroxymethyl-2-methyltrimethylene, (2-hydroxyethyl)methylene, (1-hydroxyethyl)methylene, 4-hydroxytetramethylene, 2-hydroxytetramethylene, 3-hydroxytetramethylene, 1-hydroxytetramethylene, 5-hydroxypentamethylene, 4-hydroxypentamethylene, 3-hydroxypentamethylene, 2-hydroxypentamethylene, 1-hydroxypentamethylene, 6-hydroxyhexamethylene, 5-hydroxyhexamethylene, 4-hydroxyhexamethylene, 3-hydroxyhexamethylene, 2-hydroxyhexamethylene, 1-hydroxyhexamethylene, 1,2-dihydroxytrimethylene, 2,2,4-trihydroxytetramethylene, 1,2,6-trihydroxyhexamethylene, 3,4,5-trihydroxypentamethylene groups.

Examples of the alkyl group which may have a hydroxyl group as a substituent include, in addition to the above described lower alkyl groups, linear or branched alkyl groups having 1 to 16 carbon atoms which have 1 to 3 hydroxyl groups as substituents such as a heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, 1-methylhexyl group, hexadecyl group, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxypropyl group, 2,3-dihydroxypropyl group, 4-hydroxybutyl group, 1,1-dimethyl-2-hydroxyethyl group, 5,5,4-trihydroxypentyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group, 1-hydroxyisopropyl group, and 2-methyl-3-hydroxypropyl group.

Examples of the hydroxyl group substituted alkyl group include linear or branched alkyl groups having 1 to 16 carbon atoms having 1 to 3 hydroxyl groups as substituents such as a hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxypropyl group, 2,3-dihydroxypropyl group, 4-hydroxybutyl group, 1,1-dimethyl-2-hydroxyethyl group, 5,5,4-trihydroxypentyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group, 1-hydroxyisopropyl group, and 2-methyl-3-hydroxypropyl group.

Examples of the cycloalkyl group which may have a substituent selected from the group consisting of a hydroxyl group and a lower alkyl group include, in addition to the above described cycloalkyl groups, cycloalkyl groups having 3 to 16 carbon atoms which may have 1 to 3 substituents selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 6 carbon atoms such as 2-hydroxycyclopropyl, 3-hydroxycyclobutyl, 3-hydroxycyclopentyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycycloheptyl, 4-hydroxycyclooctyl, 5-hydroxycyclononyl, 3-hydroxycyclodecyl, 4-hydroxycycloundecyl, 5-hydroxycyclododecyl, 6-hydroxycyclotridecyl, 7-hydroxycyclotetradecyl, 6-hydroxycyclopentadecyl, 8-hydroxycyclohexadecyl, 2,4-dihydroxycyclohexyl, 2,4,6-trihydroxycyclohexyl, 1-methylcyclopentyl, 2-ethylcyclopropyl, 3-n-propylcyclobutyl, 2-n-butylcyclohexyl, 4-n-pentylcycloheptyl, 4-n-hexylcyclooctyl, 2,3-dimethylcyclohexyl, 2,3,4-trimethylcyclohexyl, 2-methyl-4-hydroxycyclohexyl groups.

Examples of the phenoxy lower alkyl group include phenoxyalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a phenoxymethyl group, 2-phenoxyethyl group, 1-phenoxyethyl group, 3-phenoxypropyl group, 4-phenoxybutyl group, 1,1-dimethyl-2-phenoxyethyl group, 5-phenoxypentyl group, 6-phenoxyhexyl group, 1-phenoxyisopropyl group, and 2-methyl-3-phenoxypropyl group.

Examples of the amino lower alkoxy group which may have a lower alkyl group as a substituent include linear or branched alkoxy groups having 1 to 6 carbon atoms substituted with an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms such as aminomethoxy, 2-aminoethoxy, 1-aminoethoxy, 3-aminopropoxy, 4-aminobutoxy, 5-aminopentyloxy, 6-aminohexyloxy, 1,1-dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, methylaminomethoxy, 1-ethylaminoethoxy, 2-propylaminoethoxy, 3-isopropylaminopropoxy, 4-butylaminobutoxy, 5-pentylaminopentyloxy, 6-hexylaminohexyloxy, dimethylaminomethoxy, 2-diethylaminoethoxy, 2-diisopropylaminoethoxy, (N-ethyl-N-propylamino)methoxy, 2-(N-methyl-N-hexylamino)ethoxy groups.

Examples of the hydroxyl group substituted lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms which have 1 to 3 hydroxyl groups as substituents such as a hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 2,3-dihydroxypropyl group, 4-hydroxybutyl group, 1,1-dimethyl-2-hydroxyethyl group, 5,5,4-trihydroxypentyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group, 1-hydroxyisopropyl group, and 2-methyl-3-hydroxypropyl group.

Examples of the amino group which may have a lower alkylsulfonyl as a substituent include amino groups which may have 1 or 2 linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms as substituents such as amino, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, dimethylsulfonylamino, diethylsulfonylamino, dipropylsulfonylamino, dibutylsulfonylamino, dipentylsulfonylamino, dihexylsulfonylamino, N-methylsulfonyl-N-ethylsulfonylamino, N-ethylsulfonyl-N-propylsulfonylamino, N-methylsulfonyl-N-butylsulfonylamino, N-methylsulfonyl-N-hexylsulfonylamino groups.

Examples of the lower alkynyl group include linear or branched alkynyl groups having 2 to 6 carbon atoms include an ethynyl group, 2-propynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2-pentynyl group, and 2-hexynyl group.

Examples of the aniline group which may have a halogen atom as a substituent on the phenyl ring include anilino groups which may have 1 to 3 halogen atoms as substituents on the phenyl ring such as aniline, 2-fluoroanilino, 3-fluoroanilino, 4-fluoroanilino, 2-bromoanilino, 3-bromoanilino, 4-bromoanilino, 2-iodoanilino, 3-iodoanilino, 4-iodoanilino, 2,3-dibromoanilino, 2,4-diiodoanilino, 2,5-difluoroanilino, 2,6-dichloroanilino, 2,4,6-trichloroanilino, 2,6-difluoroanilino, 3,5-difluoroanilino, 2,6-difluoroanilino, 2-chloroanilino, 3-chloroanilino, 4-chloroanilino, 2,3-dichloroanilino, 2,4-dichloroanilino, 2,5-dichloroanilino, 3,4-dichloroanilino, 2,6-dichloroanilino, 3,5-dichloroanilino, 2,4,6-trifluoroanilino, 2,4-difluoroanilino, 3,4-difluoroanilino groups.

Examples of the piperazinyl group which may have a lower alkyl group as a substituent on the piperazine ring include piperazinyl groups which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the piperazine ring such as a (1-, 2- or 3-)piperazinyl group, 4-methyl-(1-, 2- or 3-)piperazinyl group, 2,3-dimethyl-(1 or 5-)piperazinyl group, and 2,3,4-trimethyl-(1-, 5- or 6-)piperazinyl group.

Examples of the pyrrolidinyl group which may have an oxo group as a substituent on the pyrrolidine ring include pyrrolidinyl groups which may have 1 or 2 oxo groups as substituents on the pyrrolidine ring such as a (1-, 2- or 3-)pyrrolidinyl group, 2-oxo-(1-, 3-, 4- or 5-)pyrrolidinyl group, 3-oxo-(1-, 2-, 4-5-)pyrrolidinyl group, 2,3-dioxo-(1-, 4- or 5-)pyrrolidinyl group, and 2,5-dioxo-(1-, 3-4-)pyrrolidinyl group.

Examples of the phenyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a lower alkyl group; a lower alkoxy groups which may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group which may have a lower alkyl group as a substituent; a hydroxyl group substituted lower alkyl group; a phenyl lower alkyl group; a lower alkynyl group; an amino group which may have a lower alkylsulfonyl group as a substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; an anilino group which may have a halogen atom as a substituent on the phenyl ring; a lower alkoxycarbonyl group; a piperazinyl group which may have a lower alkyl group as a substituent on the piperazine ring; a pyrrolidinyl group which may have an oxo group as a substituent on the pyrrolidine ring; a lower alkanoylamino group; a cyano group; and a phenoxy group include phenyl groups which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms; a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms; a halogen atom; an aminoalkoxy group of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms and which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atom as substituents; a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as substituents; a phenylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms; a linear or branched alkynyl group having 2 to 6 carbon atoms; an amino group which may have 1 or 2 linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms as substituents; a linear or branched alkylthio group having 1 to 6 carbon atoms; a cycloalkyl group having 3 to 16 carbon atoms; a phenylthio group; an adamantyl group; an anilino group which may have 1 to 3 halogen atoms as substituents on the phenyl ring; a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms; a piperazinyl group which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the piperazine ring; a pyrrolidinyl group which may have 1 or 2 oxo groups as substituents on the pyrrolidine ring; an amino group which may have 1 or 2 linear or branched alkanoyl groups having 2 to 6 carbon atoms; a cyano group; and a phenoxy group such as phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-isopropylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-(bromomethoxy)phenyl, 3-(2-chloroethoxy)phenyl, 4-(2,3-dichloropropoxy)phenyl, 4-(4-fluorobutoxy)phenyl, 3-(5-chloropentyloxy)phenyl, 4-(5-bromohexyloxy)phenyl, 4-(5,6-dibromohexyloxy)phenyl, 3,4-di(trifluoromethoxy)phenyl, 3,4-di(4,4,4-trichlorobutoxy)phenyl, 2,4-di(3-chloro-2-methoxypropyl)phenyl, 2,5-di(3-chloropropoxy)phenyl, 2,6-di(2,2,2-trifluoroethoxy)phenyl, 3,4,5-tri(trifluoromethoxy)phenyl, 4-(2,2,2-trichloroethoxy)phenyl, 2-methyl-4-trifluoromethoxyphenyl, 3-ethyl-4-trichloromethoxyphenyl, 2-methoxy-4-trifluoromethoxyphenyl, 3-ethoxy-4-trichloromethoxyphenyl, 2-methyl-3-trifluoromethoxy-4-trifluoromethoxyphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2,3-diphenoxyphenyl, 3,4-diphenoxyphenyl, 2,6-diphenoxyphenyl, 3,4,5-triphenoxyphenyl, 2-methyl-4-phenoxyphenyl, 3-ethyl-4-phenoxyphenyl, 2-methoxy-4-phenoxyphenyl, 3-ethoxy-4-phenoxyphenyl, 2-methyl-3-phenoxy-4-trifluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2,3-dibromophenyl, 2,4-diiodophenyl, 4-methylthiophenyl, 4-cyclohexylphenyl, 4-chloro-2-anilinophenyl, 2-(4-chloroanilino)-5-ethoxycarbonylphenyl, 4-(2-(N,N-diethylamino)ethoxy]phenyl, 4-(4-methyl-1-piperazinyl)phenyl, 4-(2-oxo-1-pyrrolidinyl)phenyl, 4-methylsulfonylaminophenyl, 4-(2-hydroxyethyl)phenyl, 4-benzylphenyl, 4-ethinylphenyl, 4-phenylthiophenyl, 4-(1-adamantyl)phenyl, 5-acetylamino-2-chlorophenyl, 3-cyanophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-propanoylaminophenyl, 3,4-dicyanophenyl, 3,4,5-tricyanophenyl groups.

Examples of the phenyl lower alkyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkyl group include, in addition to the above described phenyl lower alkyl groups, phenylalkyl groups which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a halogen atom, a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and a linear or branched alkyl group having 1 to 6 carbon atoms, and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-(2-fluorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 3,4-dibromobenzyl, 3,4-diiodobenzyl, 2,4-difluorobenzyl, 2,5-dichlorobenzyl, 2,6-dichlorobenzyl, 3,4,5-trifluorobenzyl, 3-(4-chlorophenyl)propyl, 1-(2-bromophenyl)ethyl, 4-(3-fluorophenyl)butyl, 5-(4-iodophenyl)pentyl, 6-(4-chlorophenyl)hexyl, 1,1-dimethyl-2-(3-fluorophenyl)ethyl, 2-methyl-3-(4-chlorophenyl)propyl, 2-methylbenzyl, 2-(3-methylphenyl)ethyl, 3-(4-methylphenyl)propyl, 1-(2-ethylphenyl)ethyl, 4-(3-ethylphenyl)butyl, 5-(4-ethylphenyl)pentyl, 6-(4-isopropylphenyl)hexyl, 1,1-dimethyl-2-(3-butylphenyl)ethyl, 2-methyl-3-(4-pentylphenyl)propyl, 4-hexylbenzyl, 3,4-dimethylbenzyl, 3,4-diethylbenzyl, 2,4-dimethylbenzyl, 2,5-dimethylbenzyl, 2,6-dimethylbenzyl, 3,4,5-trimethylbenzyl, 2-methoxybenzyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 4-methoxybenzyl, 1-(2-ethoxyphenyl)ethyl, 3-(3-ethoxyphenyl)propyl, 4-(4-ethoxyphenyl)butyl, 5-(4-isopropoxyphenyl)pentyl, 6-(3-butoxyphenyl)hexyl, 1,1-dimethyl-2-(4-pentyloxyphenyl)ethyl, 2-methyl-3-(4-hexyloxyphenyl)propyl, 3,4-dimethoxybenzyl, 3,4-diethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2-trifluoromethoxybenzyl, 3-trifluoromethoxybenzyl, 4-trifluoromethoxybenzyl, 2-[2-(bromomethoxy)phenyl]ethyl, 1-[3-(2-chloroethoxy)phenyl]ethyl, 3-[4-(2,3-dichloropropoxy)phenyl]propyl, 4-[4-(4-fluorobutoxy)phenyl]butyl, 5-[3-(5-chloropentyloxy)phenyl]pentyl, 6-[(4-(5-bromohexyloxy)phenyl]hexyl, 1,1-dimethyl-2-[4-(5,6-dibromohexyloxy)phenyl]ethyl, 3,4-di(trifluoromethoxy)benzyl, 3,4-di(4,4,4-trichlorobutoxy)benzyl, 2,4-di(3-chloro-2-methoxypropyl)benzyl, 2,5-di(3-chloropropoxy)benzyl, 2,6-di(2,2,2-trifluoroethoxy)benzyl, 3,4,5-tri(trifluoromethoxy)benzyl, 4-(2,2,2-trichloroethoxy)benzyl, 2-methyl-4-trifluoromethoxybenzyl, 3-ethyl-4-trichloromethoxybenzyl, 2-methoxy-4-trifluoromethoxybenzyl, 3-ethoxy-4-trichloromethoxybenzyl, 2-methyl-3-trifluoromethoxy-4-trifluoromethoxybenzyl, 2-chloro-3-methylbenzyl, 4-fluoro-2-trifluoromethoxybenzyl, 3-chloro-2-methyl-4-methoxybenzyl groups.

Examples of the phenyl lower alkyl group which has a lower alkylenedioxy group as a substituent on the phenyl ring include phenylalkyl groups which has a linear or branched alkylenedioxy group having 1 to 4 carbon atoms on the phenyl ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a 3,4-methylenedioxybenzyl group, 3,4-trimethylenedioxybenzyl group, 2-(2,3-ethylenedioxyphenyl)ethyl group, 1-(3,4-trimethylenedioxyphenyl)ethyl group, 3-(2,3-tetramethylenedioxyphenyl)propyl group, 4-(3,4-methylenedioxyphenyl)butyl group, 5-(2,3-ethylenedioxyphenyl)pentyl group, 6-(3,4-trimethylenedioxyphenyl)hexyl group, 1,1-dimethyl-2-(2,3-methylenedioxyphenyl)ethyl group, and 2-methyl-3-(3,4-ethylenedioxyphenyl)propyl group.

Examples of the amino group which may have a lower alkanoyl group as a substituent include which may have a linear or branched alkanoyl group having 1 to 6 carbon atoms as a substituent such as an amino group, N-acetylamino group, N-formylamino group, N-propionylamino group, N-butyrylamino group, N-isobutyrylamino group, N-pentanoylamino group, N-tert-butylcarbonylamino group, and N-hexanoylamino group.

Examples of the 1,2,3,4-tetrahydroquinolyl group which may have, on the tetrahydroquinoline ring, 1 to 3 substituents selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group include 1,2,3,4-tetrahydroquinolyl groups which may have, on the tetrahydroquinoline ring, 1 to 3 substituents selected from the group consisting of an oxo group, a linear or branched alkoxy group having 1 to 6 carbon atoms, and a linear or branched alkylenedioxy group having 1 to 4 carbon atoms such as (1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl, 2-oxo-(1, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl, 2-oxo-6,7-methylenedioxy-(1, 3, 4, 5, or 8-)1,2,3,4-tetrahydroquinolyl, 4-oxo-(1, 2, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl, 2,4-dioxo-(1, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl, 2,4-dioxo-6,7-methylenedioxy-(1, 3, 5, or 8-)1,2,3,4-tetrahydroquinolyl, 5,6-ethylenedioxy-(1, 2, 3, 4, 7, or 8-)1,2,3,4-tetrahydroquinolyl, 7,8-trimethylenedioxy-(1, 2, 3, 4, 5, or 6-)1,2,3,4-tetrahydroquinolyl, 6,7-tetramethylenedioxy-(1, 2, 3, 4, 5, or 8-)1,2,3,4-tetrahydroquinolyl, 5-methoxy-2-oxo-(1, 3, 4, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl, 2-oxo-6,7-ethylenedioxy-(1, 3, 4, 5, or 8-)1,2,3,4-tetrahydroquinolyl groups.

Examples of the cycloalkyl lower alkyl group include cycloalkylalkyl groups having 3 to 16 carbon atoms of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a cyclopropylmethyl group, cyclohexylmethyl group, 2-cyclopropylethyl group, 1-cyclobutylethyl group, 3-cyclopentylpropyl group, 4-cyclohexylbutyl group, 5-cycloheptylpentyl group, 6-cyclooctylhexyl group, 1,1-dimethyl-2-cyclononylethyl group, 2-methyl-3-cyclodecylpropyl group, cycloundecylmethyl group, 2-cyclododecylethyl group, 1-cyclotridecylethyl group, 3-cyclotetradecylpropyl group, 4-cyclopentadecylbutyl group, and 5-cyclodecylpentyl group.

Examples of the pyridyl lower alkyl group include pyridylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (2, 3 or 4-)pyridylmethyl group, 2-[(2, 3 or 4-)pyridyl]ethyl group, 1-[(2, 3 or 4-)pyridyl]ethyl group, 3-[(2, 3 or 4-)pyridyl]propyl group, 4-[(2, 3 or 4-)pyridyl]butyl group, 1,1-dimethyl-2-[(2, 3 or 4-)pyridyl]ethyl group, 5-[(2, 3 or 4-)pyridyl]pentyl group, 6-[(2, 3 or 4-)pyridyl]hexyl group, 1-[(2, 3 or 4-)pyridyl]isopropyl group, and 2-methyl-3-[(2, 3 or 4-)pyridyl]propyl group.

Examples of the amino group substituted lower alkyl group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkanoyl group include linear or branched alkyl groups having 1 to 6 carbon atoms which has an amino group which may have 1 or 2 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkanoyl group having 1 to 6 carbon atoms such as aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, 2-diisopropylaminoethyl, (N-ethyl-N-propylamino)methyl, 2-(N,N-dimethylamino)ethyl, 2-(N-methyl-N-hexylamino)ethyl, formylaminomethyl, acetylaminomethyl, 1-propionylaminoethyl, 2-acetylaminoethyl, 3-butyrylaminopropyl, 4-pentanoylaminobutyl, 5-hexanoylaminopentyl, 6-acetylaminohexyl, N-methyl-N-acetylaminomethyl, 2-(N-ethyl-N-propanoylamino)ethyl, (N-ethyl-N-butyrylamino)methyl, 2-(N-methyl-N-hexanoylamino)ethyl, 3-(N,N-dimethylamino)propyl groups.

Examples of the lower alkoxy lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms which have a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent such as a methoxymethyl group, 1-ethoxyethyl group, 2-methoxyethyl group, 2-propoxyethyl group, 3-isopropoxypropyl group, 4-butoxybutyl group, 5-pentyloxypentyl group, 6-hexyloxyhexyl group, 1,1-dimethyl-2-methoxyethyl group, 2-methyl-3-ethoxypropyl group, and 3-methoxypropyl group.

Examples of the 1,2,3,4-tetrahydroisoquinolylcarbonyl substituted lower alkyl group include 1,2,3,4-tetrahydroisoquinolylcarbonyl-alkyl groups of which the alkyl moiety is a linear or branched alkyl group such as (1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonylmethyl, 2-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]ethyl, 1-[((1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]ethyl, 3-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]propyl, 4-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]butyl, 1,1-dimethyl-2-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]ethyl, 5-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]pentyl, 6-[(1, 2, 3, 4, 5, 6, 7, or 8-) 1,2,3,4-tetrahydroisoquinolylcarbonyl]hexyl, 1-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]isopropyl, 2-methyl-3-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]propyl groups.

Examples of the piperidinylcarbonyl group which may have, on the piperidine ring, a substituent selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, and a furyl lower alkyl group include piperidinylcarbonyl groups which may have, on the piperidine ring, 1 to 3 substituents selected from the group consisting of an alkoxycarbonyl group of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, a phenylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, and a furylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 3, or 4-)piperidinylcarbonyl, 1-benzyl-(2, 3, or 4-)piperidinylcarbonyl, 1-(2 or 3-)furylmethyl-(2, 3, or 4-)piperidinylcarbonyl, 1-(2-phenylethyl)-(2, 3, or 4-)piperidinylcarbonyl, 1-{2-[(1 or 2-)furyl]ethyl}-(2, 3, or 4-)piperidinylcarbonyl, 1-(1-phenylethyl)-(2, 3, or 4-)piperidinylcarbonyl, 1-{3-[(1 or 2-)furyl]propyl]}-(2, 3, or 4-)piperidinylcarbonyl, 1-(3-phenylpropyl)-(2, 3, or 4-)piperidinylcarbonyl, 1-{1-[(1 or 2-)furyl]ethyl]}-(2, 3, or 4-)piperidinylcarbonyl, 1-(4-phenylbutyl)-(2, 3, or 4-)piperidinylcarbonyl, 1-{4-[(1 or 2-)furyl]-butyl]}-(2, 3, or 4-)piperidinylcarbonyl, 1-(5-phenylpentyl)-(2, 3, or 4-)piperidinylcarbonyl, 1-{5-[(1 or 2-)furyl]pentyl]}-(2, 3, or 4-)piperidinylcarbonyl, 1-(6-phenylhexyl)-(2, 3, or 4-)piperidinylcarbonyl, 1-{(6-[(1 or 2-)furyl]hexyl]}-(2, 3, or 4-)piperidinylcarbonyl, 1,2-dibenzyl-(3, 4, 5, or 6-)piperidinylcarbonyl, 1,3-di(1 or 2-)furylmethyl-(2, 4, 5, or 6-)piperidinylcarbonyl, 1,3,5-tribenzyl-(2,4, or 6-)piperidinylcarbonyl, 1,2,6-tri(1 or 2-)furylmethyl-(3, 4, or 5-)piperidinylcarbonyl, 1-benzyl-3-(1 or 2-)furylmethyl-(2, 4, 5, or 6-)piperidinylcarbonyl, 1-{1-[(1 or 2-)furyl]ethyl]}-(2, 3, or 4-)piperidinylcarbonyl, 1-methoxycarbonyl-(2, 3, or 4-)piperidinylcarbonyl, 1-ethoxycarbonyl-(2,3, or 4-)piperidinylcarbonyl, 1-propoxycarbonyl-(2, 3, or 4-)piperidinylcarbonyl, 1-butoxycarbonyl-(2, 3, or 4-) piperidinylcarbonyl, 1-tert-butoxycarbonyl-(2, 3, or 4-)piperidinylcarbonyl, 1-pentyloxycarbonyl-(2, 3, or 4-)piperidinylcarbonyl, 1-hexyloxycarbonyl-(2, 3, or 4-)piperidinylcarbonyl, 1,2-dimethoxycarbonyl-(3, 4, 5, or 6-)piperidinylcarbonyl, 1,2,6-triethoxycarbonyl-(3, 4, or 5-)piperidinylcarbonyl, 1-(1 or 2-)furylmethyl-3-tert-butoxycarbonyl-(3, 4, 5, or 6-)piperidinylcarbonyl, 1-benzyl-2-methoxycarbonyl-(2, 4, 5, or 6-)piperidinylcarbonyl, 1-(1 or 2-)furylmethyl-2,4-dimethoxycarbonyl-(3, 5, or 6-)piperidinylcarbonyl groups.

Examples of the thiazolidinyl lower alkanoyl group which may have an oxo group as a substituent on the thiazolidine ring include thiazolidinylalkanoyl groups which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and of which the alkanoyl moiety is a linear or branched alkanoyl group having 1 to 6 carbon atoms such as 2-[(2, 3, 4, or 5-)thiazolidinyl]acetyl, 3-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 2-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 4-[(2, 3, 4, or 5-)thiazolidinyl]butyryl, 5-[(2, 3, 4, or 5-)1,2,4-thiazolidinyl]pentanoyl, 6-[(2, 3, 4, or 5-)thiazolidinyl]hexanoyl, 2,2-dimethyl-3-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 2-methyl-3-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 2,4-dioxo-(3 or 5-)thiazolidinylacetyl, 3-[2-oxo-(3, 4, or 5-)thiazolidinyl]propionyl, 2-[4-oxo-(2, 3, or 5-)thiazolidinyl]propionyl, 4-[5-oxo-(2, 3, or 4-)thiazolidinyl]butyryl, 5-[2,5-dioxo-(3 or 4-)thiazolidinyl]pentanoyl, 6-[2,4,5-trioxo-3-thiazolidinyl]hexanoyl, 2-[4,5-dioxo-(2 or 3-)thiazolidinyl]acetyl, 2,2-dimethyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propionyl, 2-methyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propionyl groups.

Examples of the piperidinyl group which may be substituted on the piperidine ring with a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, a lower alkyl group, a benzoyl group and a furyl lower alkyl group include piperidinyl groups which may be substituted on the piperidine ring with 1 to 3 groups selected from the group consisting of an alkoxycarbonyl group of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, a phenylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkyl group having 1 to 6 carbon atoms, a benzoyl group, and a furylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 3, or 4-)piperidinyl, 1-benzyl-(2, 3, or 4-)piperidinyl, 1-(2 or 3-)furylmethyl-(2, 3, or 4-)piperidinyl, 1-(2-phenylethyl)-(2, 3, or 4-)piperidinyl, 1-{2-[(1 or 2-)furyl]ethyl}-(2, 3, or 4-)piperidinyl, 1-(1-phenylethyl)-(2, 3, or 4-)piperidinyl, 1-{3-[(1 or 2-)furyl]propyl]}-(2, 3, or 4-)piperidinyl, 1-(3-phenylpropyl)-(2, 3, or 4-)piperidinyl, 1-{1-[(1 or 2-)furyl]ethyl]}-(2, 3, or 4-)piperidinyl, 1-(4-phenylbutyl)-(2, 3, or 4-)piperidinyl, 1-{4-[(1 or 2-)furyl]butyl]}-(2, 3, or 4-)piperidinyl, 1-(5-phenylpentyl)-(2, 3, or 4-)piperidinyl, 1-{5-[(1 or 2-)furyl]pentyl]}-(2, 3, or 4-)piperidinyl, 1-(6-phenylhexyl)-(2, 3, or 4-)piperidinyl, 1-{6-[(1 or 2-)furyl]hexyl]}-(2, 3, or 4-)piperidinyl, 1,2-dibenzyl-(3, 4, 5, or 6-)piperidinyl, 1,3-di(1 or 2-)furylmethyl-(2, 4, 5, or 6-)piperidinyl, 1,3,5-tribenzyl-(2, 4, or 6-)piperidinyl, 1,2,6-tri(1 or 2-)furylmethyl-(3, 4, or 5-)piperidinyl, 1-benzyl-3-(1 or 2-)furylmethyl-(2, 4, 5, or 6-)piperidinyl, 1-{1-[(1 or 2-)furyl]ethyl]}-(2, 3, or 4-)piperidinyl, 1-benzoyl-(2, 3, or 4-)piperidinyl, 1,2-dibenzoyl-(3, 4, 5, or 6-)piperidinyl, 1,3,5-tribenzoyl-(2, 4, or 6-)piperidinyl, 1-methyl-(2, 3, or 4-)piperidinyl, ethyl-(2, 3, or 4-)piperidinyl, 1-propyl-(2, 3, or 4-)piperidinyl, 1-isopropyl-(2, 3, or 4-)piperidinyl, 1-butyl-(2, 3, or 4-)piperidinyl, 1-isobutyl-(2, 3, or 4-)piperidinyl, 1-tert-butyl-(2, 3, or 4-)piperidinyl, 1-pentyl-(2, 3, or 4-)piperidinyl, 1-hexyl-(2, 3, or 4-)piperidinyl, 1,2-dimethyl-(3, 4, 5, or 6-)piperidinyl, 1,2,6-trimethyl-(3, 4, or 5-)piperidinyl, 1-methyl-3-benzyl-(3, 4, 5, or 6-)piperidinyl, 1-benzoyl-2-methyl-(2, 4, 5, or 6-)piperidinyl, 1-(1 or 2-)furylmethyl-2,4-dimethyl-(3, 5, or 6-)piperidinyl, 1-methoxycarbonyl-(2, 3, or 4-)piperidinyl, 1-ethoxycarbonyl-(2, 3, or 4-)piperidinyl, 1-propoxycarbonyl-(2, 3, or 4-)piperidinyl, 1-butoxycarbonyl-(2, 3, or 4-)piperidinyl, 1-tert-butoxycarbonyl-(2, 3, or 4-)piperidinyl, 1-pentyloxycarbonyl-(2, 3, or 4-)piperidinyl, 1-hexyloxycarbonyl-(2, 3, or 4-)piperidinyl, 1,2-dimethoxycarbonyl-(3, 4, 5, or 6-)piperidinyl, 1,2,6-triethoxycarbonyl-(3, 4, or 5-)piperidinyl, 1-methyl-3-tert-butoxycarbonyl-(3, 4, 5, or 6-)piperidinyl, 1-benzoyl-2-methoxycarbonyl-(2, 4, 5, or 6-)piperidinyl, 1-(1 or 2-)furylmethyl-2,4-dimethoxycarbonyl-(3, 5, or 6-)piperidinyl, 1-benzyl-2,4-dimethoxycarbonyl-(3, 5, or 6-)piperidinyl groups.

Examples of the carbonyl lower alkyl group substituted with a group:

(hereinafter called “A group”) include A group substituted carbonylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as an A group substituted carbonylmethyl group, 2-A group substituted carbonylethyl group, 1-A group substituted carbonylethyl group, 3-A group substituted carbonylpropyl group, 4-A group substituted carbonylbutyl group, 1,1-dimethyl-2-A group substituted carbonylethyl group, 5-A group substituted carbonylpentyl group, 6-A group substituted carbonylhexyl group, 1-A group substituted carbonylisopropyl group, and 2-methyl-3-A group substituted carbonylpropyl group.

Examples of the carbonyl lower alkyl group substituted with a group:

wherein R³⁴ is an oxo group or phenyl group, and d is an integer of 0 to 3 (hereinafter called “B group”), B group substituted carbonylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a B group substituted carbonylmethyl group, 2-B group substituted carbonylethyl group, 1-B group substituted carbonylethyl group, 3-B group substituted carbonylpropyl group, 4-B group substituted carbonylbutyl group, 1,1-dimethyl-2-B group substituted carbonylethyl group, 5-B group substituted carbonylpentyl group, 6-B group substituted carbonylhexyl group, 1-B group substituted carbonylisopropyl group, and 2-methyl-3-B group substituted carbonypropyl group.

Examples of the pyrrolidinyl lower alkyl group include pyrrolidinylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (1-, 2-, or 3-)pyrrolydinylmethyl group, 2-[(1-, 2-, or 3-)pyrrolydinyl]ethyl group, 1-[(1-, 2-, or 3-)pyrrolydinyl]ethyl group, 3-[(1-, 2-, or 3-)pyrrolydinyl]propyl group, 4-[(1-, 2-, or 3-)pyrrolydinyl]butyl group, 5-[(1-, 2-, or 3-)pyrrolydinyl]pentyl group, 6-[(1-, 2-, or 3-)pyrrolydinyl]hexyl group, 1,1-dimethyl-2-[(1-, 2-, or 3-)pyrrolydinyl]ethyl group, and 2-methyl-3-[(1-, 2-, or 3-)pyrrolydinyl]propyl group.

Examples of the morpholino lower alkyl group include morpholinoalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (2-, 3- or 4-)morpholinomethyl group, 2-[(2-, 3- or 4-)morpholino]ethyl group, 1-[(2-, 3- or 4-)morpholino]ethyl group, 3-[(2-, 3- or 4-)morpholino]propyl group, 4-[(2-, 3- or 4-)morpholino]butyl group, 5-[(2-, 3- or 4-)morpholino]pentyl group, 6-[(2-, 3- or 4-)morpholino]hexyl group, 1,1-dimethyl-2-[(2-, 3- or 4-)morpholino]ethyl group, and 2-methyl-3-[(2-, 3- or 4-)morpholino]propyl group.

Examples of the phenyl lower alkenyl group include phenylalkenyl groups of which the alkenyl moiety is a linear or branched alkenyl group having 2 to 6 carbon atoms and which have 1 to 3 double bonds such as a styryl group, 3-phenyl-2-propenyl group (trivial name; cinnamyl group), 4-phenyl-2-butenyl group, 4-phenyl-3-butenyl group, 5-phenyl-4-pentenyl group, 5-phenyl-3-pentenyl group, 6-phenyl-5-hexenyl group, 6-phenyl-4-hexenyl group, 6-phenyl-3-hexenyl group, 4-phenyl-1,3-butadienyl group, and 6-phenyl-1,3,5-hexatrienyl group.

Examples of the anilinocarbonyl lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring include anilinocarbonylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the phenyl ring such as anilinocarbonylmethyl, 2-anilinocarbonylethyl, 1-anilinocarbonylethyl, 3-anilinocarbonylpropyl, 4-anilinocarbonylbutyl, 5-anilinocarbonylpentyl, 6-anilinocarbonylhexyl, 1,1-dimethyl-2-anilinocarbonylethyl, 2-methyl-3-anilinocarbonylpropyl, (4-methylanilinocarbonyl)methyl, 2-(3-methylanilinocarbonyl)ethyl, 3-(4-methylanilinocarbonyl)propyl, 1-(2-ethylanilinocarbonyl)ethyl, 4-(3-ethylanilinocarbonyl)butyl, 5-(4-ethylanilinocarbonyl)pentyl, 6-(4-isopropylanilinocarbonyl)hexyl, 1,1-dimethyl-2-(3-butylanilinocarbonyl)ethyl, 2-methyl-3-(4-pentylanilinocarbonyl)propyl, 4-hexylanilinocarbonylmethyl, 3,4-dimethylanilinocarbonylmethyl, 3,4-diethylanilinocarbonylmethyl, 2,4-dimethylanilinocarbonylmethyl, 2,5-dimethylanilinocarbonylmethyl, 2,6-dimethylanilinocarbonylmethyl, 3,4,5-trimethylanilinocarbonylmethyl groups.

Examples of the piperazinyl lower alkyl group which may have, on the piperazine ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring include piperazinylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and which may have, on the piperazine ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a phenylalkyl group which may have a linear or branched alkylenedioxy group having 1 to 4 carbon atoms as a substituent on the phenyl ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1-, 2-, or 3-)piperazinyl]methyl, 2-[(1-, 2-, or 3-)piperazinyl]ethyl, 1-[(1-, 2-, or 3-)piperazinyl]ethyl, 3-[(1-, 2-, or 3-)piperazinyl]propyl, 4-[(1-, 2-, or 3-)piperazinyl]butyl, 5-[(1-, 2-, or 3-)piperazinyl]pentyl, 6-[(1-, 2-, or 3-)piperazinyl]hexyl, 1,1-dimethyl-2-[(1-, 2-, or 3-)piperazinyl]ethyl, 2-methyl-3-[(1-, 2-, or 3-)piperazinyl]propyl, [1-methyl-(2-, 3-, or 4-)piperazinyl]methyl, 2-[1-ethyl-(2-, 3-, or 4-)piperazinyl]ethyl, 1-[4-propyl-(1-, 2-, or 3-)piperazinyl]ethyl, 3-[3-isopropyl-(1-, 2-, 4-, 5-, or 6-)piperazinyl]propyl, 4-[2-butyl-(1-, 3,4-, 5-, or 6-)piperazinyl]butyl, 5-[1-isobutyl-(2-, 3-, or 4-)piperazinyl]pentyl, 3-[4-methyl-(1-, 2-, or 3-)piperazinyl]propyl, 6-(1-tert-butyl-(2-, 3-, or 4-)piperazinyl]hexyl, 1,1-dimethyl-2-[(4-pentyl-(1-, 2-, or 3-)piperazinyl]ethyl, [1,2-dimethyl-(3-, 4-, 5-, or 6-)piperazinyl]methyl, [1,2,6-trimethyl-(3-, 4-, or 5-)piperazinyl]methyl, 2-[(4-(3,4-methylenedioxybenzyl)-(1-, 2-, or 3-)piperazinyl]ethyl groups.

Examples of the amidino lower alkyl group which may have a lower alkyl group as a substituent include amidinoalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms such as an amidinomethyl group, 2-amidinoethyl group, 1-amidinoethyl group, 3-amidinopropyl group, 4-amidinobutyl group, 5-amidinopentyl group, 6-amidinohexyl group, 1,1-dimethyl-2-amidinoethyl group, 2-methyl-3-amidinopropyl group, N,N-dimethylamidinomethyl group, 2-(N,N-dimethylamidino)ethyl group, 1-(N-methylamidino)ethyl group, 3-(N-ethylamidino)propyl group, 4-(N-n-propylamidino)propyl group, 5-(N-n-pentylamidino)pentyl group, 6-(N-n-hexylamidino)hexyl group, and (N-methyl-N-ethylamidino)methyl group.

Examples of the carbazolyl group which may have a lower alkyl group as a substituent on the carbazole ring include carbazolyl groups which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the carbazole ring such as (1-, 2-, 3-, or 4-)carbazolyl, 9-methyl-(1-, 2-, 3-, or 4-)carbazolyl, 9-ethyl-(1-, 2-, 3-, or 4-)carbazolyl, 1-ethyl-(2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-)carbazolyl, 2-n-propyl-(1-, 3-, 4-, 5-, 6-, 8-, or 9-)carbazolyl, 3-n-butyl-(1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-)carbazolyl, 4-n-pentyl-(1-, 2-, 3-, 5-, 6-, 7-, 8-, or 9-)carbazolyl, 5-n-hexyl-(1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-)carbazolyl, 6,9-dimethyl-(1-, 2-, 3-, 4-, 5-, 7-, or 8-)carbazolyl, 1,7,8-trityl-(2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-)carbazolyl groups.

Examples of the amidino group which may have a lower alkyl group as a substituent include amidino groups which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents such as an amidino group, N,N-dimethylamidino group, N-methylamidino group, N-ethylamidino group, N-n-propylamidino group, N-n-butylamidino group, N-n-pentylamidino group, N-n-hexylamidino group, N,N-diethylamidino group, and N-methyl-N-ethylamidino group.

Examples of the 5- to 7-membered saturated heterocyclic group formed by binding R³⁶ and R³⁷ each other, together with nitrogen atoms bound to them, through or not through a nitrogen atom, an oxygen atom or a sulfur atom, include a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, thiomorpholino group, and homopiperazinyl group.

Examples of the 5- to 10-membered saturated or unsaturated heterocyclic group formed by binding R¹⁴ and R¹⁵ each other, together with nitrogen atoms bound to them, through or not through a nitrogen atom, an oxygen atom or a sulfur atom, include 1,2,3,4,5,6-hexahydropyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, homopiperazinyl, homopiperidinyl, thiazolidinyl, 1,2,5,6-tetrahydropyridyl, pyrrolyl, pyrazolyl, imidazolyl, 2-pyrrolinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,2-dihydropyridyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2-dihydroisoquinolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, 3,4-dihydro-2H-1,4-benzoxadinyl, 3,4-dihydro-2H-1,4-benzothiazolidinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,2,3,1-tetrahydroquinolinyl, 1,2,3,4-tetrahydrophthalazinyl, 1,2,3,4-tetrahydroquinazolinyl, 1,2-dihydroquinoxalinyl, 3,4-dihydroquinoxalinyl, 1,4-dihydroquinoxalinyl, 1,2-dihydroquinolinyl, 1,2-dihydrophthalazinyl, 3,4-dihydrophthalazinyl, 1,2-dihydroquinazolinyl, 3,4-dihydroquinazolinyl, indazolyl, indazolinyl, 6-azabicyclo[3,2,1]octyl, aza-spiro[5,5]undecyl, thiazolidinyl groups.

Examples of the phenyl lower alkoxy group include phenylalkoxy groups of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms such as a benzyloxy group, 2-phenylethoxy group, 1-phenylethoxy group, 3-phenylpropoxy group, 4-phenylbutoxy group, 5-phenylpentyloxy group, 6-phenylhexyloxy group, 1,1-dimethyl-2-phenylethoxy group, and 2-methyl-3-phenylpropoxy group.

Examples of the phenyl substituted lower alkyl group which has 1 or 2 phenyl groups which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a lower alkanoyl group, an amino group which may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy groups; and which may have a pyridyl group on the lower alkyl group include, in addition to the above described phenyl lower alkyl groups, phenyl substituted alkyl groups which have 1 or 2 phenyls which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a linear branched alkanoyl group having 1 to 6 carbon atoms, an amino group which may have 1 or 2 linear or branched alkanoyl groups having 1 to 6 carbon atoms as substituents, a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, a cyano group, a nitro group, a phenyl group, a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a phenylalkoxy groups of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, a hydroxy group, and a linear or branched alkylenedioxy group having 1 to 4 carbon atoms; and which may have a pyridyl group on the alkyl group, of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as 1-phenyl-1-(2, 3, or 4-)pyridylmethyl, 1,1-diphenylmethyl, 1,1-di(4-fluorophenyl)methyl, 1-phenyl-1-(4-methoxyphenyl)methyl, 3,4-methylenedioxybenzyl, 3,4-ethylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 2,5-difluorobenzyl, 2,4-difluorobenzyl, 3,4-difluorobenzyl, 3,5-difluorobenzyl, 2,6-difluorobenzyl, 3-trifluoromethylbenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-cyanobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-methoxybenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 2,5-dichlorobenzyl, 3,4-dichlorobenzyl, 2,6-dichlorobenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 2-nitrobenzyl, 3-trifluoromethoxybenzyl, 4-trifluoromethoxybenzyl, 2-trifluoromethoxybenzyl, 4-methoxycarbonylbenzyl, 3-methoxycarbonylbenzyl, 4-tert-butylbenzyl, 4-ethylbenzyl, 4-isopropylbenzyl, 4-methoxy-3-chlorobenzyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methylphenyl)ethyl, 4-phenylbenzyl, 3,3-diphenylpropyl, 3-methyl-4-nitrobenzyl, 4-(4-methoxyphenyl)butyl, 2-(4-methylphenyl)ethyl, 4-tert-butoxycarbonylbenzyl, 3-chloro-6-methoxybenzyl, 4-acetylaminobenzyl, 4-nitro-3-methylbenzyl, 4-hydroxybenzyl, 3-hydroxybenzyl, 2-hydroxybenzyl, 4-tert-butyrylbenzyl, 4-benzyloxybenzyl, 4-pivaloylbenzyl, 2-(4-acetylphenyl)ethyl, 1-(3-propionylphenyl)ethyl, 3-(2-butyrylphenyl)propyl, 4-(4-pentanoylphenyl)butyl, 5-(3-hexanoylphenyl)pentyl, 6-(2,4-diacetylphenyl)hexyl, 1,1-dimethyl-2-(2,4,6-triacetylphenyl)ethyl, 2-methyl-3-(3,4-diacetylphenyl)propyl, 2-(4-aminophenyl)ethyl, 1-(3-propionylaminophenyl)ethyl, 3-(2-butyrylaminophenyl)propyl, 4-(4-pentanoylamino)phenylbutyl, 5-(hexanoylaminophenyl)pentyl, 6-(N-acetyl-N-propionylaminophenyl)hexyl, 1,1-dimethyl-2-(3,4-diaminophenyl)ethyl, 2-methyl-3-(3,4,5-triacetylaminophenyl)propyl, 2-(2-ethoxycarbonylphenyl)ethyl, 1-(3-propoxycarbonylphenyl)ethyl, 3-(4-pentyloxycarbonylphenyl)propyl, 4-(3-hexyloxycarbonylphenyl)butyl, 5-(3,4-dimethoxycarbonylphenyl)pentyl, 6-(3,4,5-triethoxycarbonylphenyl)hexyl, 1,1-dimethyl-2-(4-butoxycarbonylphenyl)ethyl, 2-methyl-3-(4-methoxycarbonylphenyl)propyl, 2-(2-cyanophenyl)ethyl, 1-(3-cyanophenyl)ethyl, 3-(4-cyanophenyl)propyl, 4-(2-cyanophenyl)butyl, 5-(3-cyanophenyl)pentyl, 6-(4-cyanophenyl)hexyl, 1,1-dimethyl-2-(2,4-dicyanophenyl)ethyl, 2-methyl-3-(2,4,6-tricyanophenyl)propyl, 2-(2-nitrophenyl)ethyl, nitrophenyl)ethyl, 3-(4-nitrophenyl)propyl, 4-(2-nitrophenyl)butyl, 5-(3-nitrophenyl)pentyl, 6-(4-nitrophenyl)hexyl, 1,1-dimethyl-2-(2,4-dinitrophenyl)ethyl, 2-methyl-3-(2,4,6-trinitrophenyl)propyl, 2-(2-phenylphenyl)ethyl, 1-(3-phenylphenyl)ethyl, 3-(4-phenylphenyl)propyl, 4-(2-phenylphenyl)butyl, 5-(3-phenylphenyl)pentyl, 6-(4-phenylphenyl)hexyl, 1,1-dimethyl-2-(2,4-diphenylphenyl)ethyl, 2-methyl-3-(2,4,6-triphenylphenyl)propyl, 2-(2-fluorophenyl)ethyl, 1-(3-bromophenyl)ethyl, 3-(4-iodophenyl)propyl, 4-(2-bromophenyl)butyl, 5-(3-chlorophenyl)pentyl, 6-(4-bromophenyl)hexyl, 1,1-dimethyl-2-(2,4-dichlorophenyl)ethyl, 2-methyl-3-(2,4,6-trifluorophenyl)propyl, 2-(2-ethylphenyl)ethyl, 1-(3-propylphenyl)ethyl, 3-(4-butylphenyl)propyl, 4-(2-pentylphenyl)butyl, 5-(3-hexylphenyl)pentyl, 6-(4-trifluoromethylphenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethylphenyl)ethyl, 2-methyl-3-[2,4,6-tri(trifluoromethyl)phenyl]propyl, 2-(2-ethoxyphenyl)ethyl, 1-(3-propoxyphenyl)ethyl, 3-(4-butoxyphenyl)propyl, 4-(2-pentyloxyphenyl)butyl, 5-(3-hexyloxyphenyl)pentyl, 6-(4-trifluoromethoxyphenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethoxyphenyl)ethyl, 2-methyl-3-(2,4,6-tri(trifluoromethoxy)phenyl]propyl, 2-(2-benzyloxyphenyl)ethyl, 1-[3-(2-phenylethoxy)phenyl]ethyl, 3-[4-(3-phenylpropoxy)phenyl]propyl, 4-[2-(4-phenylbutoxy)phenyl]butyl, 5-(3-(5-phenylpentyloxy)phenyl]pentyl, 6-[4-(6-phenylhexyloxy)phenyl]hexyl, 1,1-dimethyl-2-(2,4-dibenzyloxyphenyl)ethyl, 2-methyl-3-(2,4,6-tribenzyloxyphenyl)propyl, 2-(2-hydroxyphenyl)ethyl, 1-(3-hydroxyphenyl)ethyl, 3-(4-hydroxyphenyl)propyl, 4-(2-hydroxyphenyl)butyl, 5-(3-hydroxyphenyl)pentyl, 6-(4-hydroxyphenyl)hexyl, 1,1-dimethyl-2-(2,4-dihydroxyphenyl)ethyl, 2-methyl-3-(2,4,6-trihydroxyphenyl)propyl, 2-(3,4-methylenedioxyphenyl)ethyl, 1-(2,3-ethylenedioxyphenyl)ethyl, 3-(3,4-trimethylenedioxyphenyl)propyl, 4-(3,4-tetramethylenedioxyphenyl)butyl, 5-(3,4-methylenedioxyphenyl)pentyl, 6-(3,4-ethylenedioxyphenyl)hexyl, 1,1-dimethyl-2-(3,4-methylenedioxy)ethyl, 2-methyl-3-(3,4-methylenedioxyphenyl)propyl groups.

Examples of the pyridyl lower alkyl group which may have, on the pyridine ring, 1 to 3 substituents selected from the group consisting of a hydroxyl group and a lower alkyl group which may have a hydroxyl group as a substituent include, in addition to the above described pyridyl lower alkyl groups, pyridylalkyl groups which may have, on the pyridine ring, 1 to 3 substituents selected from the group consisting of a hydroxy group and a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 hydroxy groups as substituents, and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [2-methyl-(3, 4, 5, or 6-)pyridyl]methyl, [2-methyl-3-hydroxy-5-hydroxymethyl-(4 or 6-)pyridyl]methyl, 2-[3-ethyl-(2, 4, 5, or 6-)pyridyl]ethyl, 1-[4-propyl-(2, 3, 5, or 6-)pyridyl]ethyl, 3-[2-butyl-(3, 4, 5, or 6-)pyridyl]propyl, 4-[3-pentyl-(2, 4, 5, or 6-)pyridyl]butyl, 1,1-dimethyl-2-(4-hexyl-(2, 3, 5, or 6-)pyridyl]ethyl, 5-[2,3-dimethyl-(4, 5, or 6-)pyridyl]pentyl, 6-[2,4,6-trimethyl-(3 or 5-)pyridyl]hexyl, 1-[2-hydroxy-(2, 3, 5, or 6-)pyridyl]isopropyl, 2-methyl-3-[3-hydroxy-(2, 4, 5, or 6-)pyridyl]propyl, [2-hydroxy-(3, 4, 5, or 6-)pyridyl]methyl, 2-[3-hydroxy-(2, 4, 5, or 6-)pyridyl]ethyl, 1-[4-hydroxy-(2, 3, 5, 6-)pyridyl]ethyl, 3-[2-hydroxy-(3, 4, 5, or 6-)pyridyl]propyl, 4-[3-hydroxy-(2, 4, 5, or 6-)pyridyl]butyl, 1,1-dimethyl-2-[4-hydroxy-(2, 3, 5, or 6-)pyridyl]ethyl, 5-[2,3-dihydroxy-(4, 5, or 6-)pyridyl]pentyl, 6-[2,4,6-trihydroxy-(3 or 5-)pyridyl]hexyl, [2-hydroxymethyl-(3, 4, 5, or 6-)pyridyl]methyl, 2-[(3-(2-hydroxyethyl)-(2, 4, 5, or 6-)pyridyl]ethyl, 1-[4-(3-hydroxypropyl)-(2, 3, 5, or 6-)pyridyl]ethyl, 3-[2-(4-hydroxybutyl)-(3, 4, 5, or 6-)pyridyl]propyl, 4-[3-(5-hydroxypentyl)-(2, 4, 5, or 6-)pyridyl]butyl, 1,1-dimethyl-2-[4-(6-hydroxyhexyl)-(2, 3, 5, or 6-)pyridyl]ethyl, 5-[2,3-di(hydroxymethyl)-(4, 5, or 6-)pyridyl]pentyl, 6-[2,4,6-tri(hydroxymethyl)-(3 or 5-)pyridyl]hexyl, 1-[2-hydroxymethyl-(2, 3, 5, or 6-)pyridyl]isopropyl, 2-methyl-3-[(3-(2,3-dihydroxypropyl)-(2, 4, 5, or 6-)pyridyl]propyl, (2-methyl-3-(2,2,4-trihydroxybutyl)-(4, 5, or 6-)pyridyl]methyl, (2-methyl-5-hydroxymethyl-(3, 4, or 6-)pyridyl]methyl groups.

Examples of the pyrrolyl lower alkyl group which may have 1 to 3 lower alkyl groups as substituents on the pyrrole ring include pyrrolylalkyl groups which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms on the pyrrole and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1, 2, or 3-)pyrrolyl]methyl, 2-[(1, 2, or 3-)pyrrolyl]ethyl, 1-[(1, 2, or 3-)pyrrolyl]ethyl, 3-[(1, 2, or 3-)pyrrolyl]propyl, 4-[(1, 2, or 3-)pyrrolyl]butyl, 5-[(1, 2, or 3-)pyrrolyl]pentyl, 6-[(1, 2, or 3-)pyrrolyl]hexyl, 1,1-dimethyl-2-[(1, 2, or 3-)pyrrolyl]ethyl, 2-methyl-3-[(1, 2, or 3-)pyrrolyl]propyl, [1-methyl-(2 or 3-)pyrrolyl]methyl, 2-[2-ethyl-(1, 3, 4, or 5-)pyrrolyl]ethyl, 1-[3-propyl-(1, 2, 4, or 5-)pyrrolyl]ethyl, 3-[1-butyl-(2, 3, or 4-)pyrrolyl]propyl, 4-[2-pentyl-(1, 3, 4, 5-)pyrrolyl]butyl, 5-[3-hexyl-(1, 2, 4, or 5-)pyrrolyl]pentyl, 6-[1,2-dimethyl-(3, 4, or 5-)pyrrolyl]hexyl, 1,1-dimethyl-2-[1,2,3-trimethyl-(4 or 5-)pyrrolyl]ethyl, 2-methyl-3-[1-ethyl-2-methyl-(3, 4, or 5-)pyrrolyl]propyl groups.

Examples of the benzoxazolyl lower alkyl group include benzoxazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2, 4, 5, 6, or 7-)benzoxazolyl]methyl, 2-[(2, 4, 5, 6, or 7-)benzoxazolyl]ethyl, 1-[(2, 4, 5, 6, or 7-)benzoxazolyl]ethyl, 3-[(2, 4, 5, 6, or 7-)benzoxazolyl]propyl, 4-[(2, 4, 5, 6, or 7-)benzoxazolyl]butyl, 5-[(2, 4, 5, 6, or 7-)benzoxazolyl]pentyl, 6-[(2, 4, 5, 6, or 7-)benzoxazolyl]hexyl, 1,1-dimethyl-2-[(2, 4, 5, 6, or 7-)benzoxazolyl]ethyl, 2-methyl-3-[(2, 4, 5, 6, or 7-)benzoxazolyl]propyl.

Examples of the benzothiazolyl lower alkyl group include benzothiazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2, 4, 5, 6, or 7-)benzothiazolyl]methyl, 2-[(2, 4, 5, 6, or 7-)benzothiazolyl]ethyl, 1-[(2, 4, 5, 6, or 7-)benzothiazolyl]ethyl, 3-[(2, 4, 5, 6, or 7-)benzothiazolyl]propyl, 4-[(2, 4, 5, 6, or 7-)benzothiazolyl]butyl, 5-[(2, 4, 5, 6, or 7-)benzothiazolyl]pentyl, 6-[(2, 4, 5, 6, or 7-)benzothiazolyl]hexyl, 1,1-dimethyl-2-[(2, 4, 5, 6, or 7-)benzothiazolyl]ethyl, 2-methyl-3-[(2, 4, 5, 6, or 7-)benzothiazolyl]propyl.

Examples of the furyl lower alkyl group include furylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a [(2 or 3-)furyl]methyl group, 2-[(2 or 3-)furyl]ethyl group, 1-[(2 or 3-)furyl]ethyl group, 3-[(2 or 3-)furyl]propyl group, 4-[(2 or 3-)furyl]butyl group, 5-[(2 or 3-)furyl]pentyl group, 6-[(2 or 3-)furyl]hexyl group, 1,1-dimethyl-2-[(2 or 3-)furyl]ethyl group, and 2-methyl-3-[(2 or 3-)furyl]propyl group.

Examples of the thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring include thiazolidinylalkyl groups which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 3, 4, or 5-)thiazolidinylmethyl, 2-[(2, 3, 4, or 5-)thiazolidinyl]ethyl, 1-[(2, 3, 4, or 5-)thiazolidinyl]ethyl, 3-[(2, 3, 4, or 5-)thiazolidinyl]propyl, 4-[(2, 3, 4, or 5-)thiazolidinyl]butyl, 5-[(2, 3, 4, or 5-)thiazolidinyl]pentyl, 6-[(2, 3, 4, or 5-)thiazolidinyl]hexyl, 1,1-dimethyl-2-[(2, 3, 4, or 5-)thiazolidinyl]ethyl, 2-methyl-3-[(2, 3, 4, or 5-)thiazolidinyl]propyl, [2,4-dioxo-(3 or 5-)thiazolidinyl]methyl, 2-[2-oxo-(3, 4, or 5-)thiazolidinyl]ethyl, 1-[(4-oxo-(2, 3, or 5-)thiazolidinyl]ethyl, 3-[2-oxo-(3, 4, or 5-)thiazolidinyl]propyl, 4-[5-oxo-(2, 3, or 4-) thiazolidinyl]butyl, 5-[(2,5-dioxo-(3 or 4-)thiazolidinyl]pentyl, 6-[2,4,5-trioxo-3-thiazolidinyl]hexyl, 1-[(4,5-dioxo-(2 or 3-)thiazolidinyl]ethyl, 2-[4,5-dioxo-(2- or 3-)thiazolidinyl]ethyl, 1,1-dimethyl-2-[(2,4-dioxo-(3 or 5-)thiazolidinyl]ethyl, 2-methyl-3-[(2,4-dioxo-(3 or 5-)thiazolidinyl]propyl groups.

Examples of the thiazolidinylidene lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring include thiazolidinylidenealkyl groups which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 4, or 5-)thiazolidinylidenemethyl, (2, 4, or 5-)thiazolidinylideneethyl, (2, 4, or 5-)thiazolidinylidenepropyl, (2, 4, or 5-)thiazolidinylideneisopropyl, (2, 4, or 5-)thiazolidinylidenebutyl, (2, 4, or 5-)thiazolidinylidenepentyl, (2, 4, or 5-)thiazolidinylidenehexyl, 4,5-dioxo-2-thiazolidinylidenemethyl, 2,5-dioxo-4-thiazolidinylidenemethyl, 2,4-dioxo-5-thiazolidinylidenemethyl, 4-oxo-(2 or 5-)thiazolidinylideneethyl, 5-oxo-(2 or 4-)thiazolidinylidenepropyl, 2-oxo-(4, or 5-)thiazolidinylidenebutyl groups.

Examples of the benzoyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a cyano group, an amino group which may have a lower alkylsulfonyl group as a substituent, a halogen atom, a lower alkoxy group, a lower alkyl group which may have a halogen atom, a thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, a thiazolidinylidene lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, and a lower alkylenedioxy group include benzoyl groups which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a cyano group; an amino group which may have 1 or 2 linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms as substituents; a halogen atom; a linear or branched alkoxy group having 1 to 6 carbon atoms; a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents; a thiazolidinylalkyl group which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms; a thiazolidinylidenealkyl group which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms; and a linear or branched alkylenedioxy group having 1 to 4 carbon atoms such as benzoyl, 4-cyanobenzoyl, 3,4-methylenedioxybenzoyl, 2-aminobenzoyl, 3-aminobenzoyl, 4-aminobenzoyl, 3,4-diaminobenzoyl, 2,4,6-triaminobenzoyl, 4-methoxybenzoyl, 4-trifluoromethylbenzoyl, 4-chlorobenzoyl, 3,4-difluorobenzoyl, 2-fluorobenzoyl, 3-bromobenzoyl, 4-iodobenzoyl, 3,4-dimethoxybenzoyl, 4-fluorobenzoyl, 3-cyanobenzoyl, 2-cyanbenzoyl, 2,3-dicyanobenzoyl, 3,4,5-tricyanobenzoyl, 4-methylbenzoyl, 4-(2,4-dioxothiazolidinylmethyl)benzoyl, 4-(2,4-dioxothiazolidinylidenemethyl)benzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 2-ethylbenzoyl, 3-ethylbenzoyl, 4-ethylbenzoyl, 4-isopropylbenzoyl, 3-butylbenzoyl, 4-pentylbenzoyl, 4-hexylbenzoyl, 3,4-dimethylbenzoyl, 3,4-diethylbenzoyl, 2,4-dimethylbenzoyl, 2,5-dimethylbenzoyl, 2,6-dimethylbenzoyl, 3,4,5-trimethylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl, 4-ethoxybenzoyl, 4-isopropoxybenzoyl, 3-butoxybenzoyl, 4-pentyloxybenzoyl, 4-hexyloxybenzoyl, 3,4-diethoxybenzoyl, 2,4-dimethoxybenzoyl, 2,5-dimethoxybenzoyl, 2,6-dimethoxybenzoyl, 3,4,5-trimethoxybenzoyl, 2-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl, 4-trifluoromethylbenzoyl, 2-(bromomethyl)benzoyl, 3-(2-chloroethyl)benzoyl, 4-(2,3-dichloropropyl)benzoyl, 4-(4-fluorobutyl)benzoyl, 3-(5-chloropentyl)benzoyl, 4-(5-bromohexyl)benzoyl, 4-(5,6-dibromohexyl)benzoyl, 3,4-di(trifluoromethyl)benzoyl, 3,4-di(4,4,4-trichlorobutyl)benzoyl, 2,4-di(3-chloro-2-methylpropyl)benzoyl, 2,5-di(3-chloropropyl)benzoyl, 2,6-di(2,2,2-trifluoroethyl)benzoyl, 3,4,5-tri(trifluoromethyl)benzoyl, 4-(2,2,2-trichloroethyl)benzoyl, 2-methyl-4-trifluoromethylbenzoyl, 3-ethyl-4-trichloromethylbenzoyl, 2-methoxy-4-trifluoromethylbenzoyl, 3-ethyl-4-fluorobenzoyl, 3-ethoxy-4-trichloromethylbenzoyl, 2-methyl-3-trifluoromethyl-4-trifluoromethylbenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2-bromobenzoyl, 4-bromobenzoyl, 2-iodobenzoyl, 3-iodobenzoyl, 2,3-dibromobenzoyl, 2,4-diiodobenzoyl, 2,5-difluorobenzoyl, 2,6-dichlorobenzoyl, 2,4,6-trichlorobenzoyl, 2,4-difluorobenzoyl, 3,4-difluorobenzoyl, 3,5-difluorobenzoyl, 2,6-difluorobenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2,3-dichlorobenzoyl, 2,4-dichlorobenzoyl, 2,5-dichlorobenzoyl, 3,4-dichlorobenzoyl, 2,6-dichlorobenzoyl, 3,5-dichlorobenzoyl, 2,4,6-trifluorobenzoyl, 2,4-difluorobenzoyl, 3,4-difluorobenzoyl, 3,4-methylenedioxybenzoyl, 3,4-trimethylenedioxybenzoyl, 2,3-ethylenedioxybenzoyl, 3,4-trimethylenedioxybenzoyl, 2,3-tetramethylenedioxybenzoyl, 2,3-methylenedioxybenzoyl, 3,4-ethylenedioxybenzoyl, 2-methanesulfonylaminobenzoyl groups.

Examples of the thiazolidinyl lower alkanoyl group which may be substituted on the thiazolidine ring with 1 to 3 groups selected from the group consisting of an oxo group and a group of the formula:

wherein R^(a) and R^(b) each represent a lower alkyl group, include thiazolidinylalkanoyl groups which may be substituted on the thiazolidine ring with 1 to 3 substituents selected from the group consisting of an oxo group and a group of the formula:

wherein R^(a) and R^(b) each represent a linear or branched alkyl group having 1 to 6 carbon atoms, and of which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as 2-[(2,3,4, or 5-)thiazolidinyl]acetyl, 3-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 2-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 4-[(2, 3, 4, or 5-)thiazolidinyl]butyryl, 5-[(2, 3, 4, or 5-)thiazolidinyl]pentanoyl, 6-[(2, 3, 4, or 5-)thiazolidinyl]hexanoyl, 2,2-dimethyl-3-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 2-methyl-3-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, [2,4-dioxo-(3 or 5-)thiazolidinyl]acetyl, 3-[2-oxo-(3, 4, or 5-)thiazolidinyl]propionyl, 2-[4-oxo-(2, 3, or 5-)thiazolidinyl]propionyl, 4-[5-oxo-(2, 3, or 4-)thiazolidinyl]butyryl, 5-[2,5-dioxo-(3 or 4-)thiazolidinyl]pentanoyl, 6-[2,4,5-trioxo-3-thiazolidinyl]hexanoyl, 2-[4,5-dioxo-(2 or 3-)thiazolidinyl]acetyl, 2,2-dimethyl-3-[(2,4-dioxo-(3 or 5-)thiazolidinyl]propionyl, 2-methyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propionyl, 2-[4-oxo-2-isopropylidenehydrazono-(3 or 5-)thiazolidinyl]acetyl, 2-[2-oxo-5-isopropylidenehydrazono-(3 or 4-)thiazolidinyl]acetyl, 2-[(2,4-di(isopropylidenehydrazono)-(3 or 5-)thiazolidinyl]acetyl, 3-[2-methylidenehydrazono-(3, 4, or 5-)thiazolidinyl]propionyl, 2-[4-ethylidenehydrazono-(2, 3, or 5-)thiazolidinyl]-propionyl, 4-[(5-propylidenehydrazono-(2, 3, or 4-)thiazolidinyl]butyryl, 5-[(2,5-di(isopropyl-idenehydrazono)-(3 or 4-)thiazolidinyl]pentanoyl, 6-[2,4,5-tri(isopropylidenehydrazono)-3-thiazolidinyl]-hexanoyl, 2-[4,5-di(isopropylidenehydrazono)-(2 or 3-)thiazolidinyl]acetyl, 2,2-dimethyl-3-[4-butylidenehydrazono-(2, 3, or 5-)thiazolidinyl]-propionyl, 2-methyl-3-[5-pentylidene-(2, 3, or 4-)thiazolidinyl]propionyl, 2-(hexylidenehydrazono)-(3, 4, or 5-)thiazolidinylacetyl groups.

Examples of the lower alkyl group which may have a substituent selected from the group consisting of a hydroxyl group and a halogen atom include, in addition to the above described lower alkyl groups, linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from the group consisting of a hydroxy group and a halogen atom such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromohexyl, 2-hydroxy-3-fluoropropyl, 2,2-dichloro-3-hydroxybutyl groups.

Examples of the phenyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a carbamoyl group which may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group, a lower alkoxycarbonyl group, a carboxy group, a cyano group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a benzoyl group which may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring, and a hydroxyl group include phenyl groups which may be substituted on the phenyl group with 1 to 3 groups selected from the group consisting of a carbamoyl group which may have 1 or 2 groups selected from the group consisting of an alkoxyalkyl group of the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, a carboxy group, a cyano group, a phenyl group, a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a benzoyl group which may have 1 to 3 halogen atoms as substituents on the phenyl ring, a phenylalkyl group which may have 1 to 3 halogen atoms as substituents on the phenyl ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, and a hydroxyl group such as phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-(bromomethoxy)phenyl, 3-(2-chloroethoxy)phenyl, 4-(2,3-dichloropropoxy)phenyl, 4-(4-fluorobutoxy)phenyl, 3-(5-chloropentyloxy)phenyl, 4-(5-bromohexyloxy)phenyl, 4-(5,6-dibromohexyloxy)phenyl, 3,4-di(trifluoromethoxy)phenyl, 3,4-di(4,4,4-trichlorobutoxy)phenyl, 2,4-di(3-chloro-2-methoxypropyl)phenyl, 2,5-di(3-chloropropoxy)phenyl, 2,6-di(2,2,2-trifluoroethoxy)phenyl, 3,4,5-tri(trifluoromethoxy)phenyl, 4-(2,2,2-trichloroethoxy)phenyl, 2-methyl-4-trifluoromethoxyphenyl, 3-ethyl-4-trichloromethoxyphenyl, 2-methoxy-4-trifluoromethoxyphenyl, 3-ethoxy-4-trichloromethoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-(bromomethyl)phenyl, 3-(2-chloroethyl)phenyl, 4-(2,3-dichloropropyl)phenyl, 4-(4-fluorobutyl)phenyl, 3-(5-chloropentyl)phenyl, 4-(5-bromohexyl)phenyl, 4-(5,6-dibromohexyl)phenyl, 3,4-di(trifluoromethyl)phenyl, 3,4-di(4,4,4-trichlorobutyl)phenyl, 2,4-di(3-chloro-2-methylpropyl)phenyl, 2,5-di(3-chloropropyl)phenyl, 2,6-di(2,2,2-trifluoroethyl)phenyl, 3,4,5-tri(trifluoromethyl)phenyl, 4-(2,2,2-trichloroethyl)phenyl, 2-methyl-4-trifluoromethylphenyl, 3-ethyl-4-trichloromethylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 4-isopropoxycarbonylphenyl, 3-butoxycarbonylphenyl, 4-tert-butoxycarbonylphenyl, 4-pentyloxycarbonylphenyl, 4-hexyloxycarbonylphenyl, 3,4-dimethoxycarbonylphenyl, 3,4-diethoxycarbonylphenyl, 2,4-dimethoxycarbonylphenyl, 2,5-diethoxycarbonylphenyl, 2,6-dimethoxycarbonylphenyl, 3,4,5-triethoxycarbonylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3,4-dicyanophenyl, 3,5-dicyanophenyl, 2,4-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophenyl, 3,4,5-tricyanophenyl, 2-phenylphenyl, 3-phenylphenyl, 4-phenylphenyl, 3,4-diphenylphenyl, 3,5-diphenylphenyl, 2,4-diphenylphenyl, 2,5-diphenylphenyl, 2,6-diphenylphenyl, 3,4,5-triphenylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3, 5-1© difluorophenyl, 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2,3-dibromophenyl, 2,4-diiodophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 3-benzylphenyl, 2-(2-phenylethyl)phenyl, 4-(1-phenylethyl)phenyl, 2-(3-phenylpropyl)phenyl, 3-(4-phenylbutyl)phenyl, 4-(5-phenylpentyl)phenyl, 2-(6-phenylhexyl)phenyl, 4-(1,1-dimethyl-2-phenylethyl)phenyl, 3-(2-methyl-3-phenylpropyl)phenyl, 2-(4-fluorobenzyl)phenyl, 2-methyl-5-chlorophenyl, 2-methoxy-5-chlorophenyl, 4-(4-fluorobenzoyl)phenyl, 4-(4-fluorobenzyl)phenyl, 3-(2-chlorobenzyl)phenyl, 4-(3-chlorobenzyl)phenyl, 2-(4-chlorobenzyl)phenyl, 3-(2-(4-fluorophenyl)ethyl]phenyl, 4-[2-(4-chlorophenyl)ethyl]phenyl, 2-(3,4-dibromobenzyl)phenyl, 3-(3,4-diiodobenzyl)phenyl, 4-(2,4-difluorobenzyl)phenyl, 2-(2,5-dichlorobenzyl)phenyl, 3-(2,6-dichlorobenzyl)phenyl, 4-(3,4,5-trifluorobenzyl)phenyl, 2-[3-(4-chlorophenyl)propyl]phenyl, 3-[1-(2-bromophenyl)ethyl]phenyl, 4-[4-(3-fluorophenyl)butyl]phenyl, 2-[5-(4-iodophenyl)pentyl]phenyl, 3-[6-(4-chlorophenyl)hexyl]phenyl, 2-[1,1-dimethyl-2-(3-fluorophenyl)ethyl]phenyl, 4-[2-methyl-3-(4-chlorophenyl)propyl]phenyl, 2,4-dibenzylphenyl, 2,4,6-tribenzylphenyl, 2-chloro-4-cyanophenyl, 3-hydroxy-4-phenylphenyl, 3-ethoxycarbonyl-2-benzoylphenyl, 2-benzyl-4-methyl-6-methoxyphenyl, 4-[(2-methoxyethyl)carbamoyl]phenyl, 3-(N-ethyl-N-isopropylcarbamoyl)phenyl, 4-dimethylcarbamoylphenyl, 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, groups.

Examples of the phenyl group which has a lower alkylenedioxy group as a substituent on the phenyl ring include phenyl groups which has a linear or branched alkylenedioxy group having 1 to 4 carbon atom as a substituent on the phenyl ring such as a 3,4-methylenedioxyphenyl group, 3,4-trimethylenedioxyphenyl group, 2,3-ethylenedioxyphenyl group, 2,3-tetramethylenedioxyphenyl group, 2,3-methylenedioxyphenyl group, 3,4-ethylenedioxyphenyl group, and 2,3-trimethylenedioxyphenyl group.

Examples of the naphthyl lower alkyl group include naphthylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (1 or 2-)naphthylmethyl group, 2-[(1 or 2-)naphthyl]ethyl group, 1-[(1 or 2-)naphthyl]ethyl group, 3-[(1 or 2-)naphthyl]propyl group, 4-[(1 or 2-)naphthyl]butyl group, 5-[(1 or 2-)naphthyl]pentyl group, 6-[(1 or 2-)naphthyl]hexyl group, 1,1-dimethyl-2-[(1 or 2-)naphthyl]ethyl group, and 2-methyl-3-[(1 or 2-)naphthyl]propyl group.

Examples of the phenoxy group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a cyano group, a lower alkyl group which may have a halogen atom as a substituent, and a lower alkoxy group which may have a halogen atom as a substituent include phenoxy groups which may be substituted on the phenyl group with 1 to 3 groups selected from the group consisting of a cyano group, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as phenoxy, 2-methylphenoxy, 3-methylphenyl, 4-methylphenoxy, 2-ethylphenoxy, 3-ethylphenoxy, 4-ethylphenoxy, 4-isopropylphenoxy, 3-butylphenoxy, 4-pentylphenoxy, 4-hexylphenoxy, 3,4-dimethylphenoxy, 3,4-diethylphenoxy, 2,4-dimethylphenoxy, 2,5-dimethylphenoxy, 2,6-dimethylphenoxy, 3,4,5-trimethylphenoxy, methoxyphenoxy, 3-methoxyphenoxy, 4-methoxyphenoxy, 2-ethoxyphenoxy, 3-ethoxyphenoxy, 4-ethoxyphenoxy, 4-isopropoxyphenoxy, 3-butoxyphenoxy, 4-pentyloxyphenoxy, 4-hexyloxyphenoxy, 3,4-dimethoxyphenoxy, 3,4-diethoxyphenoxy, 2,4-dimethoxyphenoxy, 2,5-dimethoxyphenoxy, 2,6-dimethoxyphenoxy, 3,4,5-trimethoxyphenoxy, 2-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, 2-(bromomethoxy)phenoxy, 3-(2-chloroethoxy)phenoxy, 4-(2,3-dichloropropoxy)phenoxy, 4-(4-fluorobutoxy)phenoxy, 3-(5-chloropentyloxy)phenoxy, 4-(5-bromohexyloxy)phenoxy, 4-(5,6-dibromohexyloxy)phenoxy, 3,4-di(trifluoromethoxy)phenoxy, 3,4-di(4,4,4-trichlorobutoxy)phenoxy, 2,4-di(3-chloro-2-methoxypropyl)phenoxy, 2,5-di(3-chloropropoxy)phenoxy, 2,6-di(2,2,2-trifluoroethoxy)phenoxy, 3,4,5-tri(trifluoromethoxy)phenoxy, 4-(2,2,2-trichloroethoxy)phenoxy, 2-methyl-4-trifluoromethoxyphenoxy, 3-ethyl-4-trichloromethoxyphenoxy, 2-methoxy-4-trifluoromethoxyphenoxy, 3-ethoxy-4-trichloromethoxyphenoxy, 2-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 4-trifluoromethylphenoxy, 2-(bromomethyl)phenoxy, 3-(2-chloroethyl)phenoxy, 4-(2,3-dichloropropyl)phenoxy, 4-(4-fluorobutyl)phenoxy, 3-(5-chloropentyl)phenoxy, 4-(5-bromohexyl)phenoxy, 4-(5,6-dibromohexyl)phenoxy, 3,4-di(trifluoromethyl)phenoxy, 3,4-di(4,4,4-trichlorobutyl)phenoxy, 2,4-di(3-chloro-2-methylpropyl)phenoxy, 2,5-di(3-chloropropyl)phenoxy, 2,6-di(2,2,2-trifluoroethyl)phenoxy, 3,4,5-tri(trifluoromethyl)phenoxy, 4-(2,2,2-trichloroethyl)phenoxy, 2-methyl-4-trifluoromethylphenoxy, 3-ethyl-4-trichloromethylphenoxy, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 3,5-dicyanophenoxy, 3,4-dicyanophenoxy, 2,3-dicyanophenoxy, 2,4-dicyanophenoxy, 2,5-dicyanophenoxy, 2,6-dicyanophenoxy, 3,4,5-tricyanophenoxy, 2-cyano-4-methylphenoxy, 3-cyano-4-methoxyphenoxy, 3-cyano-5-trifluoromethylphenoxy, 4-cyano-3-trifluoromethoxyphenoxy groups.

Examples of the phenyl lower alkoxy group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, and a lower alkyoxy group which may have a halogen atom as a substituent include, in addition to the above described phenyl lower alkoxy groups, phenylalkoxy groups which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms such as 2,5-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 3,5-difluorobenzyloxy, 2,6-difluorobenzyloxy, 3-trifluoromethylbenzyloxy, 2-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 3,4-dimethoxybenzyloxy, 3,5-dimethoxybenzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-methylbenzyloxy, 3-methylbenzyloxy, 4-methylbenzyloxy, 3,4-dimethylbenzyloxy, 2,3-dimethylbenzyloxy, 2-methoxybenzyloxy, 3-methoxybenzyloxy, 4-methoxybenzyloxy, 2,3-dichlorobenzyloxy, 2,4-dichlorobenzyloxy, 2,5-dichlorobenzyloxy, 3,4-dichlorobenzyloxy, 2,6-dichlorobenzyloxy, 4-fluorobenzyloxy, 3-fluorobenzyloxy, 2-fluorobenzyloxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 2-trifluoromethxybenzyloxy, 4-tert-butylbenzyloxy, 4-ethylbenzyloxy, 4-isopropylbenzyloxy, 4-methoxy-3-chlorobenzyloxy, 2-(4-methoxyphenyl)ethoxy, 2-(4-fluorophenyl)ethoxy, 2-(4-chlorophenyl)ethoxy, 2-(3-methoxyphenyl)ethoxy, 2-(4-methylphenyl)ethoxy, 3-methyl-4-chlorobenzyloxy, 4-(4-methoxyphenyl)butoxy, 2-(4-methylphenyl)ethoxy, 4-tert-butoxybenzyloxy, 3-chloro-6-methoxybenzyloxy, 4-methoxy-3-methylbenzyloxy, 2-(2-fluorophenyl)ethoxy, 1-(3-bromophenyl)ethoxy, 3-(4-iodophenyl)propoxy, 4-(2-bromophenyl)butoxy, 5-(3-chlorophenyl)pentyloxy, 6-(4-bromophenyl)hexyloxy, 1,1-dimethyl-2-(2,4-dichlorophenyl)ethoxy, 2-methyl-3-(2,4,6-trifluorophenyl)propoxy, 2-(2-ethylphenyl)ethoxy, 1-(3-propylphenyl)ethoxy, 3-(4-butylphenyl)propoxy, 4-(2-pentylphenyl)butoxy, 5-(3-hexylphenyl)pentyloxy, 6-(4-trifluoromethylphenyl)hexyloxy, 1,1-dimethyl-2-(2,4-dimethylphenyl)ethoxy, 2-methyl-3-[2,4,6-tri(trifluoromethyl)phenyl]propoxy, 2-(2-ethoxyphenyl)ethoxy, 1-(3-propoxyphenyl)ethoxy, 3-(4-butoxyphenyl)propoxy, 4-(2-pentyloxyphenyl)butoxy, 5-(3-hexyloxyphenyl)pentyloxy, 6-(4-trifluoromethoxyphenyl)hexyloxy, 1,1-dimethyl-2-(2,4-dimethoxyphenyl)ethoxy, 2-methyl-3-[2,4,6-tri(trifluoromethoxy)phenyl]propoxy groups.

Examples of the 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring include 1,2,3,4-tetrahydronaphthyl substituted alkyl groups which may have 1 to 5 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the 1,2,3,4-tetrahydronaphthalene ring, and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 5, or 6-)1,2,3,4-tetrahydronaphthylmethyl, 2-[(1, 2, 5, or 6-)1,2,3,4-tetrahydronaphthyl]ethyl, 1-[(1, 2, 5, or 6-)1,2,3,4-tetrahydronaphthyl]ethyl, 3-[(1, 2, 5, or 6-)1,3,4-tetrahydronaphthyl]propyl, 4-[(1, 2, 5, or 6-)1,2,3,4-tetrahydronaphthyl]butyl, 5-[(1, 2, 5, or 6-)1,2,3,4-tetrahydronaphthyl]pentyl, 6-[(1, 2, 5, or 6-)1,2,3,4-tetrahydronaphthyl]hexyl, 1,1-dimethyl-2-[(1,2,5,6-)1,2,3,4-tetrahydronaphthyl]ethyl, 2-methyl-3-[(1,2,5, or 6-)1,2,3,4-tetrahydronaphthyl]propyl, 1,1,4,4-tetramethyl(2, 3, 5, or 6-)1,2,3,4-tetrahydronaphthylmethyl, 1,1,4,4,5-pentamethyl(2, 3, 6, 7, or 8-)1,2,3,4-tetrahydronaphthylmethyl, 1,4,4-trimethyl(2, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydronaphthylmethyl, 5,6-dimethyl(2, 3, 7, or 8-)1,2,3,4-tetrahydronaphthylmethyl, 2-[1-methyl-(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydronaphthyl]ethyl, 1-[2-ethyl-(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydronaphthyl]ethyl, 3-[3-propyl-(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydronaphthyl]propyl, 4-[(4-butyl-1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydronaphthyl]butyl, 5-[5-pentyl-(1, 2, 3, 4, 6, 7, or 8-)1,2,3,4-tetrahydronaphthyl]pentyl, 6-[6-hexyl-(1, 2, 3, 4, 5, 7, or 8-)1,2,3,4-tetrahydronaphthyl]hexyl, 1,1-dimethyl-2-[1,7-dimethyl-(1, 2, 3, 4, 5, 6, or 8-)1,2,3,4-tetrahydronaphthyl]ethyl, 2-methyl-3-[1,1,4-trimethyl-(2, 3, 4, 5, 6, 7, or 8-) 1,2,3,4-tetrahydronaphthyl]propyl groups.

Examples of the piperidinyl group which may have 1 to 3 lower alkyl groups as substituents on the piperidine ring include piperidinyl group which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the piperidine ring such as (1, 2, 3, or 4-)piperidinyl, 1-methyl-(2, 3, or 4-)piperidinyl, 1-ethyl-(2, 3, or 4-)piperidinyl, 1-propyl-(2, 3, or 4-)piperidinyl, 1-isopropyl-(2, 3, or 4-)piperidinyl, 1-butyl-(2, 3, or 4-)piperidinyl, 1-isobutyl-(2, 3, or 4-)piperidinyl, 1-tert-butyl-(2, 3, or 4-)piperidinyl, 1-pentyl-(2, 3, or 4-)piperidinyl, 1-hexyl-(2, 3, or 4-)piperidinyl, 1,2-dimethyl-(3, 4, 5, or 6-)piperidinyl, 1,2,6-trimethyl-(3, 4, or 5-)piperidinyl groups.

Examples of the quinolyl lower alkyl group include quinolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (2, 3, 4, 5, 6, 7 or 8-)quinolylmethyl group, 2-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]ethyl group, 1-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]ethyl group, 3-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]propyl group, 4-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]butyl group, 5-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]pentyl group, and 6-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]hexyl group.

Examples of the 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group include 1,2,3,4-tetrazolylalkyl groups which may have, on the tetrazole ring, a substituent selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, the 1,2,3,4-tetrazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as [(1 or 5-)1,2,3,4-tetrazolyl]methyl, 2-[(1 or 5-)1,2,3,4-tetrazolyl]ethyl, 1-[(1 or 5-)1,2,3,4-tetrazolyl]ethyl, 3-[(1 or 5-)1,2,3,4-tetrazolyl]propyl, 4-[(1 or 5-)1,2,3,4-tetrazolyl]butyl, 5-[(1 or 5-)1,2,3,4,-tetrazolyl]pentyl, 6-[(1 or 5-)1,2,3,4-tetrazolyl]hexyl, 5-[1-methyl-5-(1,2,3,4-tetrazolyl)]pentyl, 6-[1-methyl-5-(1,2,3,4-tetrazolyl)]hexyl, 5-methyl-1-(1,2,3,4-tetrazolyl)methyl, 2-[5-ethyl-1-(1,2,3,4-tetrazolyl]hexyl, 1,1-dimethyl-2-[(1 or 5-)1,2,3,4-tetrazolyl)]ethyl, 2-methyl-3-[(1 or 5-)1,2,3,4-tetrazolyl]propyl, [1-methyl-5-(1,2,3,4-tetrazolyl)]methyl, [1-ethyl-5-(1,2,3,4-tetrazolyl)]methyl, 2-[1-propyl-5-(1,2,3,4-tetrazolyl)]ethyl, 1-[1-butyl-5-(1,2,3,4-tetrazolyl)]ethyl, 3-[1-pentyl-5-(1,2,3,4-tetrazolyl)]propyl, 3-[5-propyl-1-(1,2,3,4-tetrazolyl)]propyl, 4-[5-butyl-1-(1,2,3,4-tetrazolyl)]butyl, 5-[5-pentyl-1-(1,2,3,4-tetrazolyl)]pentyl, 6-[5-hexyl-1-(1,2,3,4-tetrazolyl)]hexyl, [1-ethyl-5-(1,2,3,4-tetrazolyl)]methyl, [1-benzyl-5-(1,2,3,4-tetrazolyl)]methyl, 1-[(2-phenylethyl)-5-(1,2,3,4-tetrazolyl)]methyl, 2-[1-(3-phenylpropyl)-5-(1,2,3,4-tetrazolyl)]ethyl, 1-[(1-(4-phenylbutyl)-5-(1,2,3,4-tetrazolyl)]ethyl, 3-[(1-(5-phenylpentyl)-5-(1,2,3,4-tetrazolyl)]propyl, 4-(1-(6-phenylhexyl)-5-(1,2,3,4-tetrazolyl)]butyl, 5-[1-(1,1-dimethyl-2-phenylethyl)-5-(1,2,3,4-tetrazolyl)]methyl, 6-[(1-(2-methyl-3-phenylpropyl)-5-(1,2,3,4-tetrazolyl)]hexyl, 5-benzyl-1-(1,2,3,4-tetrazolyl)methyl, 2-(5-(1-phenylethyl)-1-(1,2,3,4-tetrazolyl)]ethyl, 3-[5-(3-phenylpropyl)-1-(1,2,3,4-tetrazolyl)]propyl, 4-[(5-(4-phenylbutyl)-1-(1,2,3,4-tetrazolyl)]butyl, 5-[(5-(5-phenylpentyl)-1-(1,2,3,4-tetrazolyl)]pentyl, 6-[5-(6-phenylhexyl)-1-(1,2,3,4-tetrazolyl)]hexyl groups.

Examples of the thiazolyl lower alkyl group which may have a phenyl group as a substituent on the thiazole ring include thiazolylalkyl groups which may have 1 or 2 phenyl groups as substituents on the thiazole ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2, 4, or 5-)thiazolyl]methyl, 2-[(2, 4, or 5-)thiazolyl]ethyl, 1-[(2, 4, or 5-)thiazolyl]ethyl, 3-[(2, 4, or 5-)thiazolyl]propyl, 4-[(2, 4, or 5-)thiazolyl]butyl, 5-[(2, 4, or thiazolyl]pentyl, 6-[(2, 4, or 5-)thiazolyl]hexyl, 1,1-dimethyl-2-[(2, 4, or 5-)thiazolyl]ethyl, 2-methyl-3-[(2, 4, or 5-)thiazolyl]propyl, [2-phenyl-(4 or 5-)thiazolyl]-methyl, 2-[(4-phenyl-(2 or 5-)thiazolyl]ethyl, 1-[(5-phenyl-(2 or 4-)thiazolyl]ethyl, 3-[(2-phenyl-(2 or 5-)thiazolyl]propyl, 4-(2,4-diphenyl-5-thiazolyl)butyl, 5-(2,5-diphenyl-4-thiazolyl)pentyl, 6-(4,5-diphenyl-2-thiazolyl)hexyl, 1,1-dimethyl-2-[2-phenyl-(4 or 5-)thiazolyl]ethyl, 2-methyl-3-[4-phenyl-(2 or 5-)thiazolyl]propyl, [4-phenyl-(2 or 5-)thiazolyl]-methyl, [5-phenyl-(2 or 4-)thiazolyl]methyl, (2,4-diphenyl-5-thiazolyl)methyl, (2,5-diphenyl-4-thiazolyl)methyl, (4,5-diphenyl-2-thiazolyl)methyl groups.

Examples of the benzoyl lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom include benzoylalkyl groups which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkoxy group having 1 to 6 carbon atoms and a halogen atom such as benzoylmethyl, 2-benzoylethyl, 1-benzoylethyl, 3-benzoylpropyl, 4-benzoylbutyl, 5-benzoylpentyl, 6-benzoylhexyl, 1,1-dimethyl-2-benzoylethyl, 2-methyl-3-benzoylpropyl, 4-fluorobenzoylmethyl, 2-chlorobenzoylmethyl, 3-chlorobenzoylmethyl, 4-chlorobenzoylmethyl, 2-(4-fluorobenzoyl)ethyl, 2-(4-chlorobenzoyl)ethyl, 3,4-dibromobenzoylmethyl, 3,4-diiodobenzoylmethyl, 2,4-difluorobenzoylmethyl, 2,5-dichlorobenzoylmethyl, 2,6-dichlorobenzoylmethyl, 3,4,5-trifluorobenzoylmethyl, 3-(4-chlorobenzoyl)propyl, 1-(2-bromobenzoyl)ethyl, 4-(3-fluorobenzoyl)butyl, 5-(4-iodobenzoyl)pentyl, 6-(4-chlorobenzoyl)hexyl, 1,1-dimethyl-2-(3-fluorobenzoyl)ethyl, 2-methyl-3-(4-chlorobenzoyl)propyl, 2-methoxybenzoylmethyl, 2-(3-methoxybenzoyl)ethyl, 2-(4-methoxybenzoyl)ethyl, 4-methoxybenzoylmethyl, 1-(2-ethoxybenzoyl)ethyl, 3-(3-ethoxybenzoyl)propyl, 4-(4-ethoxybenzoyl)butyl, 5-(4-isopropoxybenzoyl)pentyl, 6-(3-butoxybenzoyl)hexyl, 1,1-dimethyl-2-(4-pentyloxybenzoyl)ethyl, 2-methyl-3-(4-hexyloxybenzoyl)propyl, 3,4-dimethoxybenzoylmethyl, 3,4-diethoxybenzoylmethyl, 2,4-dimethoxybenzoylmethyl, 2,5-dimethoxybenzoylmethyl, 2,6-dimethoxybenzoylmethyl, 3,4,5-trimethoxybenzoylmethyl, 2-chloro-4-methoxybenzoylmethyl, 3-fluoro-5-ethoxybenzoylmethyl groups.

Examples of the piperidinyl lower alkyl group which may have a lower alkyl group as a substituent on the piperidine ring include piperidinylalkyl groups which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms on the piperidine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1, 2, 3, or 4-)piperidinyl]methyl, 2-[(1, 2, 3, or 4-)piperidinyl]-ethyl, 1-[(1, 2, 3, or 4-)piperidinyl]ethyl, 3-[(1, 2, 3, or 4-)piperidinyl]propyl, 4-[(1, 2, 3, or 4-)piperidinyl]butyl, 5-[(1, 2, 3, or 4-)piperidinyl]pentyl, 6-[(1, 2, 3, or 4-)piperidinyl]hexyl, 1,1-dimethyl-2-[(1, 2, 3, or 4-)piperidinyl]ethyl, 2-methyl-3-[(1, 2, 3, or 4-)piperidinyl]propyl, [1-methyl-(2, 3, or 4-)piperidinyl]methyl, 2-[1-ethyl-(2, 3, or 4-)piperidinyl]ethyl, 1-[4-propyl-(1, 2, or 3-)piperidinyl]ethyl, 3-[3-isopropyl-(1, 2, 4, 5, 6-)piperidinyl]propyl, 4-[2-butyl-(1, 3, 4, 5, or 6-)piperidinyl]butyl, 5-[1-isobutyl-(2, 3, or 4-)piperidinyl]pentyl, 6-[1-tert-butyl-(2, 3, or 4-)piperidinyl]hexyl, 1,1-dimethyl-2-[4-pentyl-(1 ,2, or 3-)piperidinyl]ethyl, 2-methyl-3-[1-hexyl-(2, 3, or 4-)piperidinyl]propyl, [1,2-dimethyl-(3, 4, 5, or 6-)piperidinyl]methyl, [1,2,6-trimethyl-(3, 4, or 5-)piperidinyl]methyl groups.

Examples of the imidazolyl group which may have 1 to 3 phenyl groups as substituents on the imidazole ring include imidazolyl groups which may have 1 to 3 phenyl groups as substituents on the imidazole ring such as a (1, 2, 4 or 5-)imidazolyl group, 1-phenyl-(2, 4 or 5-)imidazolyl group, 2-phenyl-(1, 4 or 5-)imidazolyl group, 4-phenyl-(1, 2 or 5-)imidazolyl group, 5-phenyl-(1, 2 or 4-)imidazolyl group, 1,2-diphenyl-(4 or 5-)imidazolyl group, 2,4-diphenyl-(1 or 5-)imidazolyl group, 4,5-diphenyl-(1 or 2-)imidazolyl group, 2,5-diphenyl-(1 or 4-)imidazolyl group, and 2,4,5-triphenyl-1-imidazolyl group.

Examples of the benzimidazolyl group which may have 1 to 3 lower alkyl groups as substituents on the benzimidazole ring include benzimidazolyl group which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the benzimidazole ring such as (1, 2, 4, 5, 6, or 7-)benzimidazolyl, 1-methyl-(2, 4, 5, 6, or 7-)benzimidazolyl, 2-ethyl-(1, 4, 5, 6, or 7-)benzimidazolyl, 4-propyl-(1, 2, 5, 6, or 7-)benzimidazolyl, 5-butyl-(1, 2, 4, 6, or 7-)benzimidazolyl, 6-pentyl-(1, 2, 4, 5, or 7-)benzimidazolyl, 7-hexyl-(1, 2, 4, 5, or 6-)benzimidazolyl, 1-ethyl-(2, 4, 5, 6, or 7-)benzimidazolyl]hexyl, 1-butyl-(2, 4, 5, 6, or 7-)benzimidazolyl, 1-isopropyl-(1, 2, 4, 5, 6, or 7-)benzimidazolyl, 1,2-dimethyl-(4, 5, 6, or 7-)benzimidazolyl, 1-methyl-4-ethyl-(2, 5, 6, or 7-)benzimidazolyl, 1-propyl-5-methyl-(2, 4, 6, or 7-)benzimidazolyl, 1,2,5-trimethyl-(2, 4, 5, 6, or 7-)benzimidazolyl groups.

Examples of the pyridyl lower alkoxy group include pyridylalkoxy group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (2, 3 or 4-)pyridylmethoxy group, 2-[(2, 3 or 4-)pyridyl]ethoxy group, 1-[(2, 3 or 4-)pyridyl]ethoxy group, 3-[(2, 3 or 4-)pyridyl]propoxy group, 4-[(2, 3 or 4-)pyridyl]butoxy group, 1-1-dimethyl-2-[(2, 3 or 4-)pyridyl]ethoxy group, 5-[(2, 3 or 4-)pyridyl]pentyloxy group, 6-[(2, 3 or 4-)pyridyl]hexyloxy group, 1-[(2, 3 or 4-)pyridyl]isopropoxy group, and 2-methyl-3-[(2, 3 or 4-)pyridyl]propoxy group.

Examples of the 1,2,3,4-tetrahydroquinolyl lower alkyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring include 1,2,3,4-tetrahydroquinolylalkyl groups which may have 1 or 2 oxo groups as substituents on the tetrahydroquinoline ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolylmethyl, 2-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]ethyl, 1-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]ethyl, 3-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]propyl, 4-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]butyl, 5-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]pentyl, 6-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]hexyl, 1,1-dimethyl-2-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]ethyl, 2-methyl-3-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]propyl, [2-oxo-(1, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]methyl, [4-oxo-(1, 2, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]methyl, [2,4-dioxo-(1, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]methyl, 2-[(2-oxo-(1, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]ethyl, 3-[4-oxo-(1, 2, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]propyl, 4-[2,4-dioxo-(1, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]butyl, 5-[(2-oxo-(1, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]pentyl, 6-[4-oxo-(1, 2, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]hexyl groups.

Examples of the 1,3,4-oxadiazolyl lower alkyl group which may have an oxo group as a substituent on the oxadiazole ring include 1,3,4-oxadiazolylalkyl groups which may have an oxo group as a substituent on the oxadiazole ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2 or 5-)1,3,4-oxadiazolylmethyl, 2-[(2 or 5-)1,3,4-oxadiazolyl]ethyl, 1-[(2 or 5-)1,3,4-oxadiazolyl]ethyl, 3-[(2 or 5-)1,3,4-oxadiazolyl]propyl, 4-[(2 or 5-)1,3,4-oxadiazolyl]butyl, 5-[(2 or 5-)1,3,4-oxadiazolyl]pentyl, 6-[(2 or 5-)1,3,4-oxadiazolyl]hexyl, 1,1-dimethyl-2-[(2 or 5-)1,3,4-oxadiazolyl]ethyl, 2-methyl-3-[(2 or 5-)1,3,4-oxadiazolyl]propyl, 2-oxo-[(3 or 5-)1,3,4-oxadiazolyl]methyl, 5-oxo-[(2 or 3-)1,3,4-oxadiazolyl]methyl, 2-[2-oxo-(3 or 5-)(1,3,4-oxadiazolyl]ethyl, 1-[5-oxo-(2 or 3-)1,3,4-oxadiazolyl]ethyl, 3-[(2 or 5-)1,3,4-oxadiazolyl]propyl, 4-[(2-oxo(3 or 5-)1,3,4-oxadiazolyl]butyl, 5-[5-oxo(2 or 3-)1,3,4-oxadiazolyl]pentyl, 6-[2-oxo(3 or 5-)1,3,4-oxadiazolyl]hexyl, 1,1-dimethyl-2-[5-oxo(2 or 3-)1,3,4-oxadiazolyl]ethyl, 2-methyl-3-[(2-oxo(3 or 5-)1,3,4-oxadiazolyl]propyl groups.

Examples of the thienyl lower alkyl group include thienylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (2 or 3-)thienylmethyl group, 2-[(2 or 3-)thienyl]ethyl group, 1-[(2 or 3-)thienyl]ethyl group, 3-[(2 or 3-)thienyl]propyl group, 4-[(2 or 3-)thienyl]butyl group, 5-[(2 or 3-)thienyl]pentyl group, 6-[(2 or 3-)thienyl]hexyl group, 1,1-dimethyl-2-[(2 or 3-)thienyl]ethyl group, and 2-methyl-3-[(2 or 3-)thienyl]propyl group.

Examples of the pyrimidinylcarbonyl group which may have an oxo group as a substituent on the pyrimidine ring include pyrimidinylcarbonyl groups which may have 1 to 3 oxo groups as substituents on the pyrimidine ring such as a (2, 3, 4 or 6-)pyrimidinylcarbonyl group, 2,6-dioxo-(1, 3, 4 or 5-)pyrimidinylcarbonyl group, 2-oxo-(1, 3, 4, 5 or 6-)pyrimidinylcarbdnyl group, 6-oxo-(1, 2, 3, 4 or 5-)pyrimidinylcarbonyl group, 4-oxo-(1, 2, 3, 4 or 6-)pyrimidylcarbonyl group, 2,4-dioxo-(1, 3, 4 or 6-)pyrimidinylcarbonyl group, and 2,4,6-trioxo-(1, 3 or 5-)pyrimidylcarbonyl group.

Examples of the lower alkoxy lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms which may have a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent such as a methoxymethoxy group, 1-ethoxyethoxy group, 2-methoxyethoxy group, 2-propoxyethoxy group, 3-isopropoxypropoxy group, 4-butoxybutoxy group, 5-pentyloxypentyloxy group, 6-hexyloxyhexyloxy group, 1,1-dimethyl-2-methoxyethoxy group, 2-methyl-3-ethoxypropoxy group, and 3-methoxypropoxy group.

Examples of the lower alkoxycarbonyl lower alkoxy group include alkoxycarbonylalkoxy groups of which both alkoxy moieties are linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxycarbonylmethoxy, ethoxycarbonylmethoxy, 2-methoxycarbonylethoxy, 2-ethoxycarbonylethoxy, 1-ethoxycarbonylethoxy, 3-methoxycarbonylpropoxy, 3-ethoxycarbonylpropoxy, 4-ethoxycarbonylbutoxy, 5-isopropoxycarbonylpentyloxy, 6-propoxycarbonylhexyloxy, 1,1-dimethyl-2-butoxycarbonylethoxy, 2-methyl-3-tert-butoxycarbonylpropoxy, 2-pentyloxycarbonylethoxy, hexyloxycarbonylmethoxy groups.

Examples of the carboxy lower alkoxy group include carboxyalkoxy groups of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms such as a carboxymethoxy group, 2-carboxyethoxy group, 1-carboxyethoxy group, 3-carboxypropoxy group, 4-carboxybutoxy group, 5-carboxypentyloxy group, 6-carboxyhexyloxy group, 1,1-dimethyl-2-carboxyethoxy group, and 2-methyl-3-carboxypropoxy group.

Examples of the phenoxy lower alkanoyl group include phenoxyalkanoyl groups of which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as a 2-phenoxyacetyl group, 3-phenoxypropionyl group, 2-phenoxypropionyl group, 4-phenoxybutyryl group, 5-phenoxypentanoyl group, 6-phenoxyhexanoyl group, 2,2-dimethyl-2-phenoxypropionyl group, and 2-methyl-3-phenoxypropionyl group.

Examples of the 1,2,3,4-tetrahydroquinolylcarbonyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring include 1,2,3,4-tetrahydroquinolylcarbonyl groups which may have 1 or 2 oxo groups as substituents on the tetrahydroquinoline ring such as a [(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]carbonyl group, [2-oxo-(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]carbonyl group, [4-oxo-(1, 2, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]carbonyl group, and [2,4-dioxo-(1, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]carbonyl group.

Examples of the 1,2,3,4-tetrahydroquinolyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring include 1,2,3,4-tetrahydroquinolyl groups which may have 1 or 2 oxo groups as substituents on the tetrahydroquinoline ring such as a (1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl group, 2-oxo-(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl group, 4-oxo-(1, 2, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl group, and 2,4-dioxo-(1, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl group.

Examples of the amino group which may have a lower alkoxycarbonyl group as a substituent include amino groups which may have a linear or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms such as an amino group, methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxycarbonylamino group, butoxycarbonylamino group, tert-butoxycarbonylamino group, pentyloxycarbonylamino group, and hexyloxycarbonylamino group.

Examples of the benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring include benzoyl groups which may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms as substituents on the phenyl ring such as a benzoyl group, 2-methoxybenzoyl group, 3-methoxybenzoyl group, 4-methoxybenzoyl group, 2-ethoxybenzoyl group, 3-ethoxybenzoyl group, 4-ethoxybenzoyl group, 4-isopropoxybenzoyl group, 3-butoxybenzoyl group, 4-pentyloxybenzoyl group, 4-hexyloxybenzoyl group, 3,4-dimethoxybenzoyl group, 3,4-diethoxybenzoyl group, 2,4-dimethoxybenzoyl group, 2,5-dimethoxybenzoyl group, 2,6-dimethoxybenzoyl group, and 3,4,5-trimethoxybenzoyl group.

Examples of the lower alkyl group which have 1 or 2 phenyls which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group, and a lower alkylthio group include, in addition to the above described phenyl lower alkyl groups, linear or branched alkyl groups which have 1 to 6 carbon atoms which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, a cyano group, a nitro group, a phenyl group, a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and a linear or branched alkylthio group having 1 to 6 carbon atoms such as 1,1-diphenylmethyl, 1,1-di(4-fluorophenyl)methyl, 1-phenyl-1-(4-methoxyphenyl)methyl, 3,3-diphenylpropyl, 2,5-difluorobenzyl, 2,4-difluorobenzyl, 3,4-difluo benzyl, 3,5-difluorobenzyl, 2,6-difluorobenzyl, 3-trifluoromethylbenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-cyanobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-methoxybenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 2,5-dichlorobenzyl, 3,4-dichlorobenzyl, 2,6-dichlorobenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 2-nitrobenzyl, 3-trifluoromethoxybenzyl, 4-trifluoromethoxybenzyl, 2-trifluoromethoxybenzyl, 4-methoxycarbonylbenzyl, 3-methoxycarbonylbenzyl, 4-tert-butylbenzyl, 4-ethylbenzyl, 4-isopropylbenzyl, 4-methoxy-3-chlorobenzyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methylphenyl)ethyl, 4-phenylbenzyl, 3,3-diphenylpropyl, 3-methyl-4-nitrobenzyl, 4-(4-methoxyphenyl)butyl, 2-(4-methylphenyl)ethyl, 4-tert-butoxycarbonylbenzyl, 3-chloro-6-methoxybenzyl, 4-nitro-3-methylbenzyl, 4-tert-butyrylbenzyl, 2-(2-ethoxycarbonylphenyl)ethyl, 1-(3-propoxycarbonylphenyl)ethyl, 3-(4-pentyloxycarbonylphenyl)propyl, 4-(3-hexyloxycarbonylphenyl)butyl, 5-(3,4-dimethoxycarbonylphenyl)pentyl, 6-(3,4,5-diethoxycarbonylphenyl)hexyl, 1,1-dimethyl-2-(4-butoxycarbonylphenyl)ethyl, 2-methyl-3-(4-methoxycarbonylphenyl)propyl, 2-(2-cyanophenyl)ethyl, 1-(3-cyanophenyl)ethyl, 3-(4-cyanophenyl)propyl, 4-(2-cyanophenyl)butyl, 5-(3-cyanophenyl)pentyl, 6-(4-cyanophenyl)hexyl, 1,1-dimethyl-2-(2,4-dicyanophenyl)ethyl, 2-methyl-3-(2,4,6-tricyanophenyl)propyl, 2-(2-nitrophenyl)ethyl, 1-(3-nitrophenyl)ethyl, 3-(4-nitrophenyl)propyl, 4-(2-nitrophenyl)butyl, 5-(3-nitrophenyl)pentyl, 6-(4-nitrophenyl)hexyl, 1,1-dimethyl-2-(2,4-dinitrophenyl)ethyl, 2-methyl-3-(2,4,6-trinitrophenyl)propyl, 2-(2-phenylphenyl)ethyl, 1-(3-phenylphenyl)ethyl, 3-(4-phenylphenyl)propyl, 4-(2-phenylphenyl)butyl, 5-(3-phenylphenyl)pentyl, 6-(4-phenylphenyl)hexyl, 1,1-dimethyl-2-(2,4-diphenylphenyl)ethyl, 2-methyl-3-(2,4,6-triphenylphenyl)propyl, 2-(2-fluorophenyl)ethyl, 1-(3-bromophenyl)ethyl, 3-(4-iodophenyl)propyl, 4-(2-bromophenyl)butyl, 5-(3-chlorophenyl)pentyl, 6-(4-bromophenyl)hexyl, 1,1-dimethyl-2-(2,4-dichlorophenyl)ethyl, 2-methyl-3-(2,4,6-trifluorophenyl)propyl, 2-(2-ethylphenyl)ethyl, 1-(3-propylphenyl)ethyl, 3-(4-butylphenyl)propyl, 4-(2-pentylphenyl)butyl, 5-(3-hexylphenyl)pentyl, 6-(4-trifluoromethylphenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethylphenyl)ethyl, 2-methyl-3-(2,4,6-tri(trifluoromethyl)phenyl]propyl, 2-(2-ethoxyphenyl)ethyl, 1-(3-propoxyphenyl)ethyl, 3-(4-butoxyphenyl)propyl, 4-(2-pentyloxyphenyl)butyl, 5-(3-hexyloxyphenyl)pentyl, 6-(4-trifluoromethoxyphenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethoxyphenyl)ethyl, 2-methyl-3-(2,4,6-tri(trifluoromethoxy)phenyl]propyl, 2-methylthiobenzyl, 3-methylthiobenzyl, 4-methylthiobenzyl, 3,4-dimethylthiobenzyl, 2,3-dimethylthiobenzyl, 2-(2-ethylthiophenyl)ethyl, 2-(4-methylthiophenyl)ethyl, 1-(3-propylthiophenyl)ethyl, 3-(4-butylthiophenyl)propyl, 4-(2-pentylthiophenyl)butyl, 5-(3-hexylthiophenyl)pentyl, 6-(4-methylthiophenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethylthiophenyl)ethyl, 2-methyl-3-[2,4,6-trimethylthiophenyl]propyl, 2-methyl-4-cyanobenzyl, 3-ethoxy-4-ethoxycarbonylbenzyl, 4-phenyl-3-nitrobenzyl, 3-fluoro-4-methoxybenzyl, 4-trifluoromethyl-3-cyanobenzyl, 3-trifluoromethoxy-3-fluorobenzyl groups.

Examples of the phenyl group which may have, on the phenyl ring, 1 to 3 groups selected from the group consisting of a linear or branched alkoxy group having 1 to 6 carbon atoms which may have a halogen atom as a substituent and a linear or branched alkyl group having 1 to 6 carbon atoms which may have a halogen atom as a substituent include phenyl groups which may have, on the phenyl ring, 1 to 3 groups selected from the group consisting of a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents and a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxy]phenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-(bromomethoxy)phenyl, 3-(2-chloroethoxy)phenyl, 4-(2,3-dichloropropoxy)phenyl, 4-(4-fluorobutoxy)phenyl, 3-(5-chloropentyloxy)phenyl, 4-(5-bromohexyloxy)phenyl, 4-(5,6-dibromohexyloxy)phenyl, 3,4-di(trifluoromethoxy)phenyl, 3,4-di(4,4,4-trichlorobutoxy)phenyl, 2,4-di(3-chloro-2-methoxypropyl)phenyl, 2,5-di(3-chloropropoxy)phenyl, 2,6-di(2,2,2-trifluoroethoxy)phenyl, 3,4,5-tri(trifluoromethoxy)phenyl, 4-(2,2,2-trichloroethoxy)phenyl, 2-methyl-4-trifluoromethoxyphenyl, 3-ethyl-4-trichloromethoxyphenyl, 2-methoxy-4-trifluoromethoxyphenyl, 3-ethoxy-4-trichloromethoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-(bromomethyl)phenyl, 3-(2-chloroethyl)phenyl, 4-(2,3-dichloropropyl)phenyl, 4-(4-fluorobutyl)phenyl, 3-(5-chloropentyl)phenyl, 4-(5-bromohexyl)phenyl, 4-(5,6-dibromohexyl)phenyl, 3,4-di(trifluoromethyl)phenyl, 3,4-di(4,4,4-trichlorobutyl)phenyl, 2,4-di(3-chloro-2-methylpropyl)phenyl, 2,5-di(3-chloropropyl)phenyl, 2,6-di(2,2,2-trifluoroethyl)phenyl, 3,4,5-tri(trifluoromethyl)phenyl, 4-(2,2,2-trichloroethyl)phenyl, 2-methyl-4-trifluoromethylphenyl, 3-ethyl-4-trichloromethylphenyl groups.

Examples of the pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent include pyrrolidinylalkyl groups which may have, on the pyrrolidine ring, 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as substituents and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1, 2, or 3-)pyrrolidinyl]methyl, 2-[(1, 2, or 3-)pyrrolidinyl]-ethyl, 1-[(1, 2, or 3-)pyrrolidinyl]ethyl, 3-[(1, 2, or 3-)pyrrolidinyl]propyl, 4-[(1, 2, or 3-)pyrrolidinyl]-butyl, 5-[(1, 2, or 3-)pyrrolidinyl]pentyl, 6-[(1,2, or 3-)pyrrolidinyl]hexyl, 1,1-dimethyl-2-[(1, 2, or 3-)pyrrolidinyl]ethyl, 2-methyl-3-[(1, 2, or 3-)pyrrolidinyl]propyl, [1-methyl-(2 or 3-)pyrrolidinyl]methyl, 2-[2-ethyl-(1, 3, 4, or 5-)pyrrolidinyl]ethyl, 1-[3-propyl-(1, 2, 4, or 5-)pyrrolidinyl]ethyl, 3-[1-butyl-(2 or 3-)pyrrolidinyl]propyl, 4-[2-pentyl-(1, 3, 4, or 5-)pyrrolidinyl]butyl, 5-[3-hexyl-(1, 2, 4, or 5-)pyrrolidinyl]pentyl, 6-[1,2-dimethyl-(3, 4, or 5-)pyrrolidinyl]hexyl, 1,1-dimethyl-2-[1,2,3-trimethyl-(4 or 5-)pyrrolidinyl]ethyl, 2-methyl-3-[(1-ethyl-2-methyl-(3, 4, or 5-)pyrrolidinyl]propyl, [1-(2-hydroxyethyl)-(2 or 3-)pyrrolidinyl]methyl, [2-hydroxymethyl-(1, 3, 4, or 5-)pyrrolidinyl]methyl, 2-[(2-hydroxymethyl-(1, 3, 4, or 5-)pyrrolidinyl]ethyl, 1-[(3-(3-hydroxypropyl)-(1, 2, 4, or 5-)pyrrolidinyl]ethyl, 3-[(1-(4-hydroxybutyl)-(2 or 3-)pyrrolidinyl]propyl, 4-[(2-(5-hydroxypentyl)-(1, 3, 4, or 5-)pyrrolidinyl]butyl, 5-[(3-(6-hydroxyhexyl)-(1, 2, 4, or 5-)pyrrolidinyl]pentyl, 6-[1,2-dihydroxymethyl-(3, 4, or 5-)pyrrolidinyl]hexyl, 1,1-dimethyl-2-[(1,2,3-trihydroxymethyl-(4 or 5-)pyrrolidinyl]ethyl, 2-methyl-3-[2-(1,2-hydroxyethyl)-(1, 3, 4, or 5-)pyrrolidinyl]propyl, [2-(2,3,4-trihydroxybutyl)-(1, 3, 4, or 5-)pyrrolidinyl]methyl groups.

Examples of the amino substituted lower alkyl group which may have a substituent selected from the group consisting of a phenyl group and a lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms substituted with an amino group which may have 1 or 2 substituents selected from the group consisting of a phenyl group and a linear or branched alkyl group having 1 to 6 carbon atoms such as aminomethyl, 2-aminomethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, N,N-diethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, 2-diisopropylaminoethyl, (N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl, phenylaminomethyl, 1-phenylaminoethyl, 2-phenylaminoethyl, 3-phenylaminopropyl, 4-phenylaminobutyl, 5-phenylaminopentyl, 6-phenylaminohexyl, N-methyl-N-phenylaminomethyl, 2-(N-ethyl-N-phenylamino)ethyl, (N-ethyl-N-phenylamino)methyl, 2-(N-methyl-N-phenylamino)ethyl groups.

Examples of the tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group include tetrahydrofurylalkyl groups which may have a hydroxyl group as a substituent on the lower alkyl group and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2 or 3-)tetrahydrofuryl]methyl, 2-[(2 or 3-)tetrahydrofuryl]ethyl, 1-[(2 or 3-)tetrahydrofuryl]ethyl, 3-[(2 or 3-)tetrahydrotetrahydrofuryl]propyl, 4-[(2 or 3-)tetrahydrofuryl]butyl, 5-[(2 or 3-)tetrahydrofuryl]pentyl, 6-[(2 or 3-)tetrahydrofuryl]hexyl, 1,1-dimethyl-2-[(2 or 3-)tetrahydrofuryl]ethyl, 2-methyl-3-[(2 or 3-)tetrahydrofuryl]propyl, 1-hydroxy-1-[(2 or 3-)tetrahydrofuryl]methyl, 2-hydroxy-2-[(2 or 3-)tetrahydrofuryl]ethyl, 2-hydroxy-1-[(2 or 3-)tetrahydrofuryl]ethyl, 3-hydroxy-3-[(2 or 3-)tetrahydrotetrahydrofuryl]propyl, 4-hydroxy-4-[(2 or 3-)tetrahydrofuryl]butyl, 5-hydroxy-5-[(2 or 3-)tetrahydrofuryl]pentyl, 6-hydroxy-6-[(2 or 3-)tetrahydrofuryl]hexyl, 2-hydroxy-1,1-dimethyl-2-[(2 or 3-)tetrahydrofuryl]ethyl, 3-hydroxy-2-methyl-3-[(2 or 3-)tetrahydrofuryl]propyl groups.

Examples of the phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group include, in addition to the above described phenoxy lower alkyl groups, phenoxyalkyl groups which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a nitro group and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 2-methylphenoxymethyl, 3-methylphenoxymethyl, 4-methylphenoxymethyl, 3,4-dimethylphenoxymethyl, 2,3-dimethylphenoxymethyl, 3,4,5-trimethylphenoxymethyl, 2-(2-ethylphenoxy)ethyl, 2-(3-methylphenoxy)ethyl, 2-(4-methylphenoxy)ethyl, 1-(3-propylphenoxy)ethyl, 3-(4-butylphenoxy)propyl, 4-(2-pentylphenoxy)butyl, 5-(3-hexylphenoxy)pentyl, 6-(4-methylphenoxy)hexyl, 1,1-dimethyl-2-(2,4-dimethylphenoxy)ethyl, 2-methyl-3-(2,4,6-trimethylphenoxy)propyl, 2-(4-nitro-3-methylphenoxy)ethyl, 4-nitrophenoxymethyl, 3-nitrophenoxymethyl, 2-nitrophenoxymethyl, 2-(2-nitrophenoxy)ethyl, 2-(4-nitrophenoxy)ethyl, 1-(3-nitrophenoxy)ethyl, 3-(4-nitrophenoxy)propyl, 4-(2-nitrophenoxy)butyl, 5-(3-nitrophenoxy)pentyl, 6-(4-nitrophenoxy)hexyl, 1,1-dimethyl-2-(2,4-dinitrophenoxy)ethyl, 2-methyl-3-(2,4,6-trinitrophenoxy)propyl.

Examples of the phenyl lower alkanoyl group include phenylalkanoyl groups of which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as a 2-phenylacetyl group, 3-phenylpropionyl group, 2-phenylpropionyl group, 4-phenylbutyryl group, 5-phenylpentanoyl group, 6-phenylhexanoyl group, 2,2-dimethyl-3-phenylpropionyl group, and 2-methyl-3-phenypropionyl group.

Examples of the 5- to 7-membered saturated heterocyclic group formed by mutually binding R²⁰ and R²¹, R²² and R²³, R²⁶ and R²⁷, R²⁹ and R³⁰ or R³² and R³³ together with the nitrogen atoms bound to them, through or not through a nitrogen atom, a oxygen atom or a sulfur atom, include a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, thiomorpholino group, and homopiperazinyl group.

Examples of the phenoxy lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring include, in addition to the above described phenoxy lower alkyl groups, phenoxyalkyl groups which may have, on the phenyl ring, 1 to 3 linear or branched alkyls having 1 to 6 carbon atoms as substituents and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 2-methylphenoxymethyl, 3-methylphenoxymethyl, 4-methylphenoxymethyl, 3,4-dimethylphenoxymethyl, 2,3-dimethylphenoxymethyl, 3,4,5-trimethylphenoxymethyl, 2-(2-ethylphenoxy)ethyl, 2-(4-methylphenoxy)ethyl, 1-(3-propylphenoxy)ethyl, 3-(4-butylphenoxy)propyl, 4-(2-pentylphenoxy)butyl, 5-(3-hexylphenoxy)pentyl, 6-(4-methylphenoxy)hexyl, 1,1-dimethyl-2-(2,4-dimethylphenoxy)ethyl, 2-methyl-3-(2,4,6-trimethylphenoxy)propyl groups.

Methods for producing the compound of the present invention will be described below.

The compound of the present invention of the general formula (1) which have various Ys is produced, for example, as shown by the following reaction formulas 1 to 4.

In the formula, R¹, R², X₁ and A are the same as described before, Y₁ represents an —O— group, an —S— group or an —NH group, and X₂ represents a halogen atom.

The reaction between the compound (2) and the compound (3) is generally carried out in an appropriate solvent or without a solvent, and in the presence or absence of a basic compound.

Examples of the inert solvent used include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, and hexamethylphosphoric acid triamide, and a mixture thereof.

Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, sodium hydride, potassium hydride, potassium, sodium, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate, and sodium n-butoxide, and organic bases such as pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), and a mixture thereof.

When the reaction is carried out in the presence of a basic compound, the basic compound is used in an amount typically equimolar to the compound (2), and preferably 1 to 10 times of the compound (2) on a molar basis.

The compound (3) is used in an amount typically at least equimolar to the compound (2), and preferably 1 to 10 times of the compound (2) on a molar basis.

The reaction is carried out typically at −30 to 200° C., and preferably at about −30 to 150° C., and is generally completed in about 5 minutes to 80 hours.

To this reaction system, an alkali metal halide such as sodium iodide or potassium iodide may be added, and a phase-transfer catalyst may be added.

Examples of the phase-transfer catalyst include quaternary ammonium salts substituted with a group selected from the group consisting of a linear or branched alkyl group having 1 to 18 carbon atoms, a phenyl lower alkyl group which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and a phenyl group, such as tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogensulfite, tributylmethylammonium chloride, tributylbenzylammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride, methyltrihexylammonium chloride, benzyldimethyloctadecanylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethylammonium chloride, phenyltriethylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride; phosphonium salts substituted with a linear or branched having 1 to 18 carbon atoms such as tetrabutylphosphonium chloride; and pyridinium salts substituted with a linear or branched alkyl group having 1 to 18 carbon atoms such as 1-dodecanylpyridinium chloride. These phase-transfer catalysts are used singly or in a combination of two or more.

Typically the phase-transfer catalyst is used in an amount of 0.1 to 1 times of the compound (2), and preferably 0.1 to 0.5 times of the compound (2).

The compound (1a), wherein Y₁ represents an —NH group, may also be produced by reacting the compound (2) with the compound (3) in the presence of an acid in place of a base. Examples of the acid used here include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid. These acids are used singly or as a mixture of two or more.

The compound (1), wherein Y represents an —N(R⁵)— group, and R⁵ is R⁵ other than a hydrogen atom, may be produced from the corresponding compound (1) wherein Y represents an —NH— group, as shown in the following reaction formula 2.

wherein R¹, R², X₁, A and X₂ are the same as described above, R^(5a) represents a lower alkyl group, phenyl lower alkyl, group or cycloalkyl group, R^(5b) represents a hydrogen atom, lower alkyl group, phenyl group or phenyl lower alkyl group, R^(5c) represents a lower alkanoyl group or benzoyl group. R^(B) represents a hydrogen atom or lower alkyl group, and R^(5b) and R^(B), together with carbon atoms bound to these groups, may form a cycloalkyl ring by binding each other, provided that the alkyl moiety in the —CHR^(B)R^(5b) group of the compound (1d) has 1 to 6 carbon atoms.

The reaction of the compound (1b) with the compound (4) is carried out under the similar condition as that for the reaction of the compound (2) with the compound (3) as shown by the above described reaction formula 1.

The reaction of the compound (1b) with the compound (5) is carried out, for example, in the presence of a reducing agent without a solvent or with an appropriate solvent. Hereinafter, this method is called “method A”.

Examples of the solvent used here include water, lower alcohols such as, methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, acetonitrile, fatty acids such as formic acid, and acetic acid, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, aromatic hydrocarbons such as benzene, toluene, and xylene, and halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, and a mixture thereof.

Examples of the reducing agent include fatty acids and alkali metal salts thereof such as formic acid, sodium formate, and sodium acetate, hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetyloxyborohydride, and aluminum lithium hydride, or a mixture of these hydride reducing agents, and catalytic hydrogen reducing agents such as palladium black, palladium-carbon, platinum oxide, platinum black, and Raney nickel.

In using a fatty acid or an alkali metal salt thereof such as formic acid, sodium formate, or sodium acetate as a reducing agent, the appropriate reaction temperature is typically from room temperature to about 200° C., and preferably about 50 to about 150° C., and the reaction is completed generally in about 10 minutes to 10 hours. It is preferable to use a fatty acid or an alkali metal salt thereof in a large excess amount with respect to the compound (1b).

In using a hydride reducing agent, the appropriate reaction temperature is typically −80 to 100° C., and preferably −80 to 70° C., and the reaction is completed in general in 30 minutes to 60 hours. The hydride reducing agent is used in an amount typically 1 to 20 times of the compound (1b), and preferably 1 to 6 times of the compound (1b) on a molar basis. Especially in using aluminum lithium hydride as a hydride reducing agent, it is preferable to employ an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme, or an aromatic hydrocarbon such as benzene, toluene, or xylene. To the reaction system, an amine such as trimethylamine, triethylamine, and N-ethyldiisopropylamine, or molecular sieves such as Molecular Sieves 3A (MS-3A) or Molecular Sieves 4A (MS-4A) may be added.

In using a catalytic hydrogen reducing agent, the reaction is preferably carried out in a hydrogen atmosphere typically at a normal pressure to about 20 atm, and preferably at a normal atmosphere to about 10 atm, or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate, at a temperature of typically −30 to 100° C., and preferably 0 to 60° C. The above described reaction is in general completed in about 1 to 12 hours. The catalytic hydrogen reducing agent is used typically in an amount of about 0.1% to 40% by weight, and about 1 to 20% by weight based on the compound (1b).

In the reaction of the compound (1b) with the compound (5), the compound (5) is typically used in an amount at least equimolar to the compound (1b), and preferably used in an equal amount to a large excess amount of compound (5) on a molar basis.

When the compound (5), wherein R^(B) and R^(5b) are mutually bound together with the carbon atoms which bind to these groups to form a cycloalkyl ring, is used as a starting material, and the hydride reducing agent is used to carry out the reaction, cycloalkyloxytrialkylsilane such as [(1-ethoxycyclopropyl)oxy]trimethylsilane may be used in place of the compound (5) as the starting material to produce the above described compound (5) in the reaction system.

The compound (1d) may be produced by reacting the compound (1b) with compound (5) under the reaction condition similar to the reaction condition of the compound (1f) with hydroxylamine of the later described reaction formula 3, and then reducing the resulting compound represented by the general formula:

wherein R¹, R², X₁, R^(B) and R^(5b) are the same as described above. A reaction condition similar to that of the method A may be applied to this reducing reaction.

The reaction of the compound (1b) with the compound (6) is carried out by a method for reacting the compound (1b) with carboxylic acid of the compound (6) in a typical reaction for producing an amide bond. Known reactions for producing an amide bond may be applied to this reaction for producing an amide bond. Specific methods thereof include: (a) a mixed acid anhydride method, specifically, a method of reacting an alkylhalocarboxylic acid with the carboxylic acid (6) to prepare a mixed acid anhydride, and then reacting the amine (1b) with the mixed acid anhydride; (b) an active ester method, specifically, a method of preparing, from the carboxylic acid (6), an active ester such as a phenyl ester, p-nitrophenyl ester, hydroxysuccinimide ester, or 1-hydroxybenzotriazole ester, or an active amide with benzoxazoline-2-thione, and then reacting the active ester or amide with the amine (1b); (c) a carbodiimide method, specifically, a method of condensation reaction of wherein the carboxylic acid (6) with the amine (1b) in the presence of an activator such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), or carbonyldiimidazole; (d) other methods, for example, a method of preparing carboxylic anhydride from the carboxylic acid (6) by the action of a dehydrator such as acetic anhydride, and then reacting the carboxylic anhydride with the amine (1b), a method of reacting an ester of the carboxylic acid (6) with a lower alcohol with the amine (1b) at a high pressure and a high temperature, and a method of reacting an acid halide of the carboxylic acid (6), that is, carboxylic acid halide, with the amine (1b).

The mixed acid anhydride used in the mixed anhydride method (a) described above, may be obtained by a typical Schotten-Baumann reaction, and the compound of the present invention of the general formula (1e) can be produced by reacting the amine (2) with the mixed acid anhydride without isolation.

The Schotten-Baumann reaction described above is carried out in the presence of a basic compound.

The basic compounds used include compounds commonly used in Schotten-Baumann reaction, for example, organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, diethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7, and 1,4-diazabicyclo[2.2.2]octane (DABCO), and inorganic bases such as carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, potassium hydride, sodium hydride, potassium, sodium, sodium amide, and metal alcoholates such as sodium methylate and sodium ethylate. These basic compounds are used singly or in a combination of two or more. The reaction is carried out at typically about −20 to 100° C., and preferably about 0 to 50° C., and the reaction time is about 5 minutes to 10 hours, and preferably about 5 minutes to 2 hours.

The resulting mixed acid anhydride is reacted with the amine (1b) at typically about −20 to 150° C., preferably about 10 to 50° C., and the reaction time is about 5 minutes to 1.0 hours, and preferably about 5 minutes to 5 hours.

The mixed acid anhydride method is, in general, carried out in a solvent. Any of the solvent conventionally used for the mixed acid anhydride method may be used. Specific examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate, ethyl acetate, and isopropyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric acid triamide, and a mixture thereof.

Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chlorformate, ethyl bromoformate, and isobutyl chloroformate.

In the mixed acid anhydride method, it is typically preferable to use the carboxylic acid (6), alkylhalocarboxylic acid and the amine (1b) equimolar to each other. However, each of alkyl halocarboxylic acid and the carboxylic acid (6) may be used 1 to 1.5 times of the amine (1b) on a molar basis, respectively.

In the above described method (c) of condensation reaction in the presence of an activator, the reaction is carried out in an appropriate solvent in the presence or absence of a basic compound. Any of the solvents and basic compounds used in the reaction in the other methods (d) described above of reacting carboxylic acid halide with the amine may be used for this reaction. It is appropriate to use the activator in an amount typically at least equimolar to the compound (1b), and preferably 1 to 5 times of the compound (1b) on a molar basis. When WSC is used as an activator, the reaction may be carried out advantageously by adding 1-hydroxybenzotriazole and/or an acid such as hydrochloric acid. This reaction is carried out at typically about −20 to 180° C., and preferably about 0 to 150° C., and is completed typically in about 5 minutes to 90 hours.

In the other method (d) described above, wherein the amine (1b) is reacted with carboxylic acid halide, the reaction is carried out in an appropriate solvent in the presence of a basic compound. As such a basic compound, known basic compounds may be widely used, and, for example, any of compounds used for the Shotten-Baumann reaction described above may be used. Examples of the solvent include, in addition to the solvents used in the mixed acid anhydride method described above, alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, acetonitrile, pyridine, acetone, and water. The ratio of the amine (1b) to the carboxylic acid halide in the reaction is not specified and may be appropriately selected in a wide range. Typically, the former may be used in an amount at least about equimolar to the latter, and preferably about 1 to 5 times of the latter on a molar basis. This reaction is carried out at typically about −20 to 180° C., and preferably about 0 to 150° C., and is completed typically in 5 minutes to 50 hours.

Further, the reaction for producing an amide bond shown in the above described reaction formula 2 may be carried out by reacting the carboxylic acid (6) and the amine (1b) in the presence of a condensation agent of a phosphorus compound such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric acid azide, or bis(2-oxo-3-oxazolidinyl)phosphinic chloride. The condensation agent described above is used singly or in a combination of two or more.

The above described reaction is carried out, in the presence of the solvent and the basic compound which are used in the method for reacting the carboxylic acid halide with the amine (1b) described above, at typically about −20 to 150° C., and preferably about 0 to 100° C., and is completed typically in 5 minutes to about 30 hours. The condensation agent and the carboxylic acid (6) may be used respectively in an amount at least about equimolar to the amine (1b), and preferably about 1 to 2 times of the amine (1b) on a molar basis.

The compound (1), wherein Y represents a —CH(OH)— or —C(═N—OH) group, is produced from the corresponding compound wherein Y represents a —CO— group, as shown in the reaction formula 3.

wherein R¹, R², X₁ and A are the same as described above.

The compound (1g) is produced by reducing the compound (1f).

In the reducing reaction described above, a reducing method employing a hydride reducing agent is favorably used. Examples of the reducing agent used include aluminum lithium hydride, sodium borohydride, borane, diborane, and lithium borohydride-trimethoxyborane. These reducing agents are used singly or in a mixture of two or more. The reducing agent may be used in an amount typically at least equimolar to the compound (1f), and preferably 1 to 15 times of the compound (1f) on a molar basis. This reducing reaction is typically carried out in an appropriate solvent, for example, water, a lower alcohol such as methanol, ethanol, or isopropanol, an ether such as tetrahydrofuran, diethyl ether, diisopropyl ether, or diglyme, or a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride, or a mixture thereof, at about −60 to 150° C., preferably from about −30 to 100° C., in general for about 10 minutes to 40 hours. In the case where aluminum lithium hydride or borane is used as the reducing agent, it is preferable to use an anhydrous solvent of tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, or the like.

The compound (1h) is produced by reacting the compound (1f) and hydroxylamine in an appropriate inert solvent in the presence or absence of a basic compound.

Examples of the basic compound used in this reaction include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, and potassium carbonate, fatty acid alkali metal salts such as sodium acetate, organic bases such as piperidine, piperidinium acetate, triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds may be used singly or in a mixture of two or more.

Any of inert solvents which do not have adverse effects on the reaction may be used. Examples thereof include water, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, dimethyl sulfoxide, N,N-dimethylformamide, and hexamethyl phosphate triamide, and a mixture thereof.

Hydroxylamine is used in an amount typically at least equimolar to the compound (1f), and preferably 1 to 5 times of the compound (1f) on a molar basis. The reaction temperature is typically at room temperature to 200° C., and preferably about 50 to 150° C., and the reaction is in general completed in about 5 minutes to 30 hours.

The compound (1), wherein Y represents an —S(O)n group (n=1 or 2), is produced from the corresponding compound wherein Y represents an —S— group, as shown in the reaction formula 4.

wherein R¹, R², X₁ and A are the same as described above, A₁₆ represents a -A group or a -A₁₀-T₂-COOR^(59a) group, T₂ represents an —N(R¹⁷)—B₃— group, a —B¹⁹—N(R¹⁸) group, a —B₄— group, a -Q-B₅— group, a —B₆—N— (R¹⁹)—B₇— group, a —CO—B₁₀— group, a —CH(OH)—B₁₁— group, a —B_(23a)—CO— group, or a direct bond, wherein R¹⁷, B₃, B₁₉, R¹⁸, B₄, B₅, B₆, R¹⁹, B₇, B₁₀ and B₁₁ are the same as described above, A¹⁰ represents a group of the formula:

wherein R³ and p are the same as described above, provided that the a is bound to a —S group or a —S(O)j group, and the b is bound to -T₂, R^(59a) is a hydrogen atom or a lower alkyl group, and j is 1 or 2.

The reaction for converting the compound (1zzzz) into the compound (1aaaaa) is carried out in an appropriate solvent and in the presence of an oxidizing agent.

Examples of the solvent include water, fatty acids such as formic acid, acetic acid, and trifluoroacetic acid, alcohols such as methanol and ethanol, and halogenated hydrocarbons such as chloroform and dichloromethane, and a mixture thereof.

Examples of the oxidizing agent include peracids such as performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, and o-carboxyperbenzoic acid, hydrogen peroxide, sodium metaperidodate, dichromic acid, dichromates such as sodium dichromate and potassium dichromate, permanganic acid, permanganates such as sodium permanganate and potassium permanganate, and lead salts such as lead tetraacetate. These oxidizing agents are used singly or in a mixture of two or more.

The oxidizing agent is appropriately used in an amount typically at least equimolar to the compound (1zzzz), and preferably 1 to 2 times of the compound (1zzzz) on a molar basis. In the oxidizing reaction which converts a sulfur atom into a sulfonyl group (j=2), it is appropriate to use the oxidizing agent in an amount typically at least two times of the compound (1zzzz), and preferably 2 to 4 times of the compound (1zzzz) on a molar basis.

The above described reaction is carried out at typically −10 to 150° C., and preferably about −10 to 100° C. and is, in general, completed in about 1 to 100 hours.

The compound of the present invention, which has the general formula (1) with various As, is produced, for example, as shown in the following reaction formulas 5 to 36.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ represents an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group which may have an oxo group as a substituent on the pyrimidine ring, a 1,2,4-oxadiazolyl lower alkyl group which may have an lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, or a -(T)₁-NR¹⁴R¹⁵ group, wherein T is a lower alkylene group and l is 1, is produced by reacting the compound (7) with the compound (8) as shown in the reaction formula 5.

wherein R¹, R² Y₁ and X₁ are the same as described above, A₁ represents a group of the formula:

wherein R³ and p are the same as described above, R^(37a) represents a —B₂₁—X₂ group, B₂₁ represents a lower alkylene group, and X₂ is the same as described above, and A₂ represents a group of the formula:

wherein R³ and p are the same as described above, R³⁰ represents a —B₂₁—R^(4a) group, B₂₁ is the same as described above, R^(4a) represents an imidazolyl group, a 1,2,4-triazolyl group, a 1,2,3-triazolyl group, a 1,2,5-triazolyl group, a pyrazolyl group, a pyrimidinyl group which has an oxo group as a substituent on the pyrimidine ring, a 1,2,4-oxadiazolyl group which may have as a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl group which may have an oxo group as a substituent on the thiazolidine ring, or an —NR¹⁴R¹⁵ group, and R¹⁴ and R¹⁵ are the same as described above.

The reaction of the compound (7) with the compound (8) is carried out under the reaction condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ is an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group which has an oxo group as a substituent on the pyrimidine ring, a 1,2,4-oxadiazolyl lower alkyl group which has a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group which has an oxo group as a substituent on the thiazolidin ring, or a (T)₁-NR¹⁴R¹⁵ group, wherein T is a lower alkylene group and l is 1, is also produced by reacting the compound (8) with the compound (9) as shown in the reaction formula 6.

wherein R¹, R², X₁ and Y₁ and R^(4a) are the same as described above, A₃ represents a group of the formula:

wherein R³ and p are the same as described above, R³⁹ represents a (B₂)_(f)COR^(A) group, B₂₁ is the same as described above, R^(A) represents a hydrogen atom or a lower alkyl group, and f represents 0 or 1, and A₄ represents a group of the formula:

wherein R³ and p are the same as described above, R⁴⁰ represents a —(B₂₁)_(f)CHR^(A)R^(4a) group, and B₂₁, R^(A), f and R^(4a) are the same as described above, provided that the alkyl moiety of the —(B₂₁)_(f)CHR^(A)R^(4a) group has not more than 6 carbon atoms.

The reaction of the compound (9) with the compound (8) is carried out under the same condition as in the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ represents a 3,5-dioxoisooxazolidinyl lower alkylidene group which may have an oxo group as a substituent on the 3,5-dioxoisooxazolidine ring, is produced by reacting the compound (11) with the compound (10) as shown in the reaction formula 7.

wherein R¹, R², X₁ and Y are the same as described above, A⁵ represents a group of the formula:

wherein R² and p are the same as described above, R⁴¹ represents a —B₂₂ (CO₂R⁴³)(CO₂R⁴⁴) group, B₂₂ represents a lower alkylidene group, and R⁴² and R⁴⁴ represent a lower alkyl group, and A⁶ represents a group of the formula:

wherein R³ and p are the same as described above, and R⁴² represents

wherein B₂₂ is the same as described above.

The reaction of the compound (10) with the compound (11) is carried out under the same condition as that of the reaction which converts the compound (1f) into the compound (1h) of the reaction formula 3.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ represents a group of the formula:

is produced from the compound (13), as shown in the reaction formula 8.

wherein R¹, R², X₁, Y and R¹³ are the same as described above, A₇ represents of the formula:

wherein R³ and p are the same as described above, and R⁴⁵ represents a halogen atom, A₈ represents a group of the formula:

wherein R³ and p are the same as described above, and R⁴⁶ represents

wherein R¹³ is the same as described above, A⁹ represents a group of the formula:

wherein R³ and p are the same as described above, and R⁴⁷ represents a group of the formula:

wherein R¹³ is the same as described above, and A^(8a) represents a group of the formula:

wherein R³ and p are the same as described above, and R^(46′) represents a group

wherein R¹³ is the same as described above.

The reaction of the compound (13) with the compound (12) is carried out in an appropriate inert solvent in the presence of a basic compound.

Examples of the basic compound used here include such as sodium, potassium, magnesium, sodium hydride, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate, and potassium tert-butoxide, and alkyl and aryl lithiums or lithium amides such as methyl lithium, n-butyl lithium, phenyl lithium, and lithium diisopropylamide. These basic compounds are used singly or in a mixture of two or more.

The basic compound is appropriately used in an amount typically at least equimolar to the compound (13), and preferably 1 to 5 times of the compound (13) on a molar basis.

Examples of the inert solvent used include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, aliphatic hydrocarbons such as n-hexane, heptane, and cyclohexane, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, dimethylsulfoxide, and N,N-dimethylformamide, and a mixture thereof.

The reaction is carried out at typically about −90 to 150° C., and preferably about −90 to 120° C., and is completed in general in about 10 minutes to 10 hours.

The compound (12) is appropriately used in an amount typically at least equimolar to the compound (13), and preferably 1 to 5 times of the compound (13) on a molar basis.

The reaction which converts the compound (11) into the compound (1m) is carried out in an appropriate inert solvent and in the presence of an acid.

Examples of the acid used here include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as sulfonic acids including p-toluenesulfonic acid. These acids are used singly or in a mixture of two or more.

It is appropriate to use the acid typically in an amount at least equimolar to the compound (11), and preferably in an equal amount to a large excess amount with respect to the compound (11) on a molar basis.

Any of the inert solvents used in the reaction of the compound (13) with the compound (12) may be used in this reaction.

This reaction is suitably carried out at typically room temperature to 200° C., preferably room temperature to about 150° C., and is completed in general in about 1 to 20 hours.

The reaction which converts the compound (11) into the compound (11′) is carried out in an appropriate solvent and in the presence of an acid and a catalyst.

Examples of the solvent used include water, lower alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, diisopropyl ether, diglyme, and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, acetonitrile, dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, and N-methylpyrrolidone, and a mixture thereof.

Examples of the acid used here include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as boron trifluoride diethyl etherate, formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid.

Examples of the catalyst include alkylsilane compounds such as triethylsilane.

The acids and the catalysts described above are respectively used typically in an amount about 0.01 to 5 times of the compound (11), and preferably about 0.01 to 1 time of the compound (11) on a molar basis.

The above described reaction is carried out at about room temperature to 200° C., and preferably about room temperature to 150° C., and is completed in general in about 1 to 10 hours.

The reaction which converts the compound (11) into the compound (11′) may be carried out in an appropriate solvent and in the presence of a catalytic hydrogen reducing agent.

Examples of the solvent used include water, fatty acids such as acetic acid, alcohols such as methanol, ethanol, and isopropanol, aliphatic hydrocarbons such as n-hexane, alicyclic hydrocarbons such as cyclohexane, ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, monoglyme, diglyme, and 1,4-dioxane, esters such as methyl acetate, ethyl acetate, and butyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and a mixture thereof.

Examples of the catalytic hydrogen reducing agent include palladium, palladium-black, palladium-carbon, palladium hydroxide-carbon, rhodium-alumina, platinum, platinum oxide, copper chromite, Raney nickel, and palladium acetate.

The catalytic hydrogen reducing agent is used typically in an amount of 0.01 to 1 times of the compound (11) on a weight basis.

The above described reaction favorably proceeds at typically about −20 to 100° C., and preferably about 0 to 80° C., and is completed generally in about 0.5 to 20 hours, and the hydrogen pressure is typically at 1 to 10 atm.

It is preferable to add a mineral acid such as hydrochloric acid to this reaction system.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ represents a group of the formula:

wherein R¹³ represents a group other than a hydrogen atom, is produced from the corresponding compound wherein R¹³ is a hydrogen atom, as shown in the following reaction formula 9.

wherein R¹, R², X₁, Y, A₁₀, R^(A), R^(13a) and X₂ are the same as described above, provided that the a and the b of A₁₀ are bound to Y and the piperidinyl group, respectively, R^(13b) represents a lower alkyl group which may have a halogen atom as a substituent, a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a piperazinylcarbonyl lower alkyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or a morpholinocarbonyl substituted lower alkyl group, R^(13c) represents a lower alkanoyl group which may have a halogen atom as a substituent, a lower alkoxy carbonyl group, a benzoyl group, a morpholino substituted alkanoyl group, a piperazinyl lower alkanoyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group on the phenyl ring; or an imidazolyl lower alkanoyl group, and R^(13d) represents a hydrogen atom, a lower alkyl group which may have a halogen atom as a substituent, a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, a phenyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl group, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a piperazinylcarbonyl lower alkyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or a morpholinocarbonyl substituted lower alkyl group, provided that the alkyl moiety of the side chain (—CHR^(A)R^(13d)) of the compound (1q) has not more than 6 carbon atoms.

The reaction of the compound (1n-1) with the compound (13′) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1n-1) with the compound (14) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (1n-1) with the compound (15) is carried out under the condition to similar that of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

Also, the reaction of the compound (1n-2) with the compound (13′) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2, the reaction of the compound (1n-2) with the compound (14) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2, and the reaction of the compound (1n-2) with the compound (15) is carried out under the condition to similar that of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the reaction formula 9, the hydrolysis of the compounds (1o-1) and (1o-2), wherein R^(13b) represents a lower alkoxycarbonyl lower alkyl group, may produce the corresponding compounds (1o-1) and (1o-2), wherein R^(13b) represents a carboxy lower alkyl group.

In the reaction formula 9, the hydrolysis of compounds (1p-1) and (1p-2), wherein R^(13c) represents a lower alkoxycarbonyl group, may produce the corresponding compounds (1p-1) and (1p-2), wherein R^(13c) is a hydrogen atom.

The hydrolysis reaction (hereinafter this hydrolysis reaction is called “hydrolysis B”) may be carried out in an appropriate solvent or without a solvent, in the presence of an acidic or basic compound.

Examples of the solvent used include water, lower alcohols such as methanol, ethanol, isopropanol, and tert-butanol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, and diglyme, fatty acids such as acetic acid and formic acid, esters such as methyl acetate and ethyl acetate, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, dimethylsulfoxide, N,N-dimethylformamide, and hexamethylphosphoric acid triamide, and a mixture thereof.

Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid, sulfonic acids including p-toluenesulfonic acid, and Lewis acids such as boron tribromide and boron trichloride. These acids are used singly or in a mixture of two or more.

Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. These basic compounds are used singly or in a mixture of two or more.

The hydrolysis reaction is favorably carried out at typically about 0 to about 200° C., and preferably about 0 to 150° C., and is completed in general in about 10 minutes to 50 hours.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ represents a group of the formula:

wherein R¹³ represents an imidazolyl lower alkyl group, is produced as shown in the following reaction formula 10.

wherein R¹, R², X₁, Y, A₁₀, R^(13a), B₂₁ and X₂ are the same as described above, provided that the a and b of A₁₀ are bound to Y and the piperidinyl group, respectively.

The reaction of the compound (1r-1) with the compound (16) with and the reaction of the compound (1r-2) with the compound (16) are carried out under the condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ represents a group of the formula:

wherein R¹³ represents a morpholino substituted alkanoyl group, a piperazinyl lower alkanoyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which has a lower alkylenedioxy group as a substituent on the phenyl ring, or an imidazolyl lower alkanoyl group, may be produced from the corresponding compound, wherein R¹³ represents a lower alkanoyl group which may have a halogen atom as a substituent, as shown in the following reaction formula 11.

wherein R¹, R², X₁, Y, R^(13a), B₂₁ and X₂ are the same as described above, and R^(47′) is a morpholino group, a piperazinyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or an imidazolyl group, provided that the a and b of A₁₀ are bound to Y and the piperidinyl group, respectively.

The reaction of the compound (1t-1) with the compound (17) and the reaction of the compound (1t-2) with the compound (17) are carried out under the condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ represents a group of the formula:

wherein R¹³ represents a piperazinylcarbonyl lower alkyl group which is substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or a morpholinocarbonyl substituted lower alkyl group, is produced from the corresponding compound, wherein R¹³ is a carboxy group, as shown in the following reaction formula 12.

wherein R¹, R², X₁, Y, A₁₀, R^(13a), and B₂₁, are the same as described above, R⁴⁸ is a piperazinyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or a morpholino group, provided that the a and b of A₁₀ are bound to Y and the piperidinyl group, respectively.

The reaction of the compound (1v-1) with the compound (18) and the reaction of the compound (1v-2) with the compound (18) are carried out under the condition similar to that of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ represents -(T)₁-NR¹⁴R¹⁵, is produced as shown in the reaction formulas 13 and 14.

In the formula, R¹, R², X₁, Y, A₁₀, X₂, l, R¹⁴ and R¹⁵ are the same as described above, T₁ is a lower alkylene group, —COB₈—, —SO₂— or a —CH(OH)—B₉—, and B⁸ and B⁹ are the same as described above, provided that, in the compounds (35) and (1pp), the a and b of A₁₀ are bound to Y and -(T₁)₁, respectively.

The reaction of the compound (35) with the compound (36) is carried out in the reaction condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (35), wherein l is 0, may also be produced by reacting the corresponding compound (35) with the compound (36) in an appropriate solvent in the presence of a basic compound and a catalyst.

Any of the solvents and basic compounds which are used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used here.

Examples of the catalyst to be used include various metal complexes as well as various combinations of a metal complex with ligand. Examples of the metal complex include, for instance, palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium (0) and the like. Examples of the ligand include, for instance, R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (R-BINAP), S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), RAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (RAC-BINAP), t-butylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and the like.

The catalyst is appropriately used in an amount typically at least equimolar to the compound (35), and preferably 1 to 5 times of the compound (35) on a molar basis.

This reaction is carried out at typically about 0 to 200° C., and preferably about 0 to 150° C., and is completed in general in about 1 to 60 hours. This reaction is called “reaction C” hereinafter.

In the formula, R², X₁, Y, A₁₀, T₂, R¹⁴ and R¹⁵ are the same as described above, provided that, in the compounds (37) and (1qq), the a and b of A₁₀ are bound to Y and T₂, respectively, and R⁹⁵ represents R¹ or a halogen atom.

The reaction of the compound (37) with the compound (36) is carried out in the reaction condition similar to that of the reaction of the compound (1b) with, the compound (6) in the above described reaction formula 2.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ represents -(T)₁-NR¹⁴R¹⁵, and l represents 0, may also be produced by the method shown in the reaction formula 15.

wherein R¹, R², X₁, Y, R^(A), X₂, T, l, and A₁₀, are the same as described above, R¹⁹ is the same group as R¹⁵ defined in (15), (22), (23), (27) and (36a), R^(49a) is R¹⁵ defined in (2) to (5), (7), (8), (10), (11), (13), (14), (16) to (21), (24), (25), (26), (26a), (27a), (28a), (29a), (30a), (31a), (32a), (33a), (34a), (35a), or (37a), a phenoxycarbonyl group and a lower alkylsulfonyl group, R^(49b) represents a hydrogen atom, an alkyl group which may have a hydroxyl group as a substituent, a phenoxy lower alkyl group, a phenyl lower alkyl group which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkyl group, a phenyl group which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkyl group, a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, a phenyl group which may have a lower alkylenedioxy group on the phenyl ring, a lower alkoxycarbonyl substituted lower alkyl group, a carboxy substituted lower alkyl group, a cycloalkyl lower alkyl group, a cycloalkyl group, a pyridyl lower alkyl group, a pyridyl group, an amino group substituted lower alkyl group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkanoyl group, a lower alkoxy lower alkyl group, an imidazolyl group, an imidazolyl lower alkyl group, a 1,2,3,4-tetrahydroisoquinolylcarbonyl substituted lower alkyl group, an A group-substituted carbonyl lower alkyl group, a pyrrolidinyl group, a pyrrolidinyl lower alkyl group, a morpholino group, a morpholino lower alkyl group, an anilinocarbonyl lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring, a piperazinyl group which may have, on the piperazine ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, a piperazinyl lower alkyl group which may have, on the piperazine ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, an amidino group which may have a lower alkyl group as a substituent, an amidino lower alkyl group which may have a lower alkyl group as a substituent, a B group substituted carbonyl lower alkyl group, or a cyano substituted lower alkyl group, R^(14a) represents a hydrogen atom or a lower alkyl group which may have a hydroxyl group as a substituent, and R³⁴, d, R³⁶, R³⁷ and B₂₀ are the same as described above, provided that, in the compounds (1rr), (1ss), (1ss′) and (1ss′), the a and b of A₁₀ are bound to Y and N, respectively, and, in the compound (1ss′), the CHR^(A)R^(49b) moiety of the side chain, (—Y-A₁₀N(R^(14a))(CHR^(A)R^(49b)) has not more than 6 carbon atoms.

The reaction of the compound (1rr) with the compound (38a) is carried out under the condition to similar that of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1rr) with the compound (38) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (1rr) with the compound (38b) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2 described above.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ represents a -(T)₁-NR¹⁴R¹⁵ group, l represents 1, and T represents a —CH(OH)—B₉— group, may also be produced by the method shown in the following reaction formula 16.

wherein R¹, R², X₁, A₁₀, Y, B₈, B₉, R¹⁴, and R¹⁵ are the same as described above, provided that, in the compounds (1tt) and (1uu), the a and b of A₁₀ are bound to Y and B₈ or B₉, respectively.

The reaction which converts the compound (1tt) into the compound (1uu) is carried out under the similar condition similar to that of the reaction which converts the compound (1f) into the compound (1g) of the above described reaction formula 3.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ represents a -(T)₁-NR¹⁴R¹⁵ group, l represents 1, and T represents a —CH(OH)—B₁₁—CO— group, may also be produced by the method shown in the following reaction formula 17.

wherein R¹, R², X₁, A₁₀, Y, B₁₀, B₁₁, R¹⁴ and R¹⁵ are the same as described above, provided that, in the compounds (1vv) and (1ww), the a and b of A₁₀ are bound to Y and a —COB₁₀ or —CH(OH)B₁₁— group, respectively.

The reaction which converts the compound (1vv) into the compound (1ww) is carried out under the condition similar to that of the reaction which converts the compound (1f) into the compound (1g) of the above described reaction formula 3.

The compound (1), wherein A represents a group of the formula:

wherein R⁴ is a -(T)₁NR¹⁴R¹⁵ group, and R¹⁴ and R¹⁵ are bound with each other to form a 5- to 10-membered saturated or unsaturated heterocyclic group which has various substituents thereon, may be produced as shown in the following reaction formulas 18 to 20, 22, 24 to 31, and 34 to 36.

In the formula, R¹, R², R^(B), X₁, Y, T, l, A₁₀ and X₂ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l,

respectively;

R^(41b) and R^(15a) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one secondary amine thereon; R^(14c) and R^(15b) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one tertiary amine thereon substituted with R⁵⁰; R^(14d) and R^(15c) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one tertiary amine thereon substituted with R⁵¹; R^(14e) and R^(15d) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one tertiary amine thereon substituted with a R⁵²(R^(B))CH— group; R^(14f) and R^(15e) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one tertiary amine thereon substituted with a group of the formula:

R⁵⁰ is the same substituent of the heterocyclic ring, which is formed by R¹⁴ and R¹⁵ bound each other, as the above described (28), (30), (31), (32), (33), (34), (36), (37), (38), (41), (43), (44), (45), (47), (49) (provided that t is 1), (50) (provided that o is 0), (51), (52), (53), (54), (55), (56), (57), (58), (59), (60), (62), (63), (64), (65), (66), (70), (77), (79), (82), (83), (87), (88a), or (90a): R⁵¹ is the same substituent of the heterocyclic group, which is formed by R¹⁴ and R¹⁵ bound each other, as the above described (35), (39), (40), (42), (50) (provided that o is 1), (67), (75), (76), (77), (78), (80), (81) or (84) (provided that s is 0); R⁵² is a hydrogen atom, a lower alkyl group which has 1 or 2 phenyls which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a lower alkanoyl group, an amino group which may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group and which may have a pyridyl group on the lower alkyl group, a phenyl group which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a lower alkanoyl group, an amino group which have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxy group, and a lower alkylenedioxy group, a pyridyl lower alkyl group which may be substituted on the pyridine ring with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a lower alkyl group which may have a hydroxyl groups as a substituent, a pyridyl group which may be substituted on the pyridine ring with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a lower alkyl group which may have a hydroxyl group as a substituent, a pyrrolyl lower alkyl group which may have 1 to 3 lower alkyl groups as substituents on the pyrrole ring, a pyrrolyl group which may have 1 to 3 lower alkyl groups as substituents on the pyrrole ring, a benzoxazolyl lower alkyl group, a benzoxazolyl group, a benzthiazolyl lower alkyl group, a benzothiazolyl group, a furyl lower alkyl group, a furyl group, a lower alkyl group which may have a substituent selected from the group consisting of a hydroxyl group and a halogen atom, a naphtyl lower alkyl group, a naphthyl group, a phenoxy lower alkyl group, a —B₁₂CO—NR²⁰R²¹ group; a —B₁₃NR²²R²³ group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a 1,2,3,4-tetrahydronaphthyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a quinolyl lower alkyl group, a quinolyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,3,4-tetrazolyl group which may have, on the tetrazole ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a thiazolyl lower alkyl group which may have a phenyl group as a substituent on the thiazole ring, a thiazolyl group wherein may have a phenyl group as a substituent on the thiazole ring, a benzoyl lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom, a piperidinyl lower alkyl group which may have a lower alkoxy group as a substituent on the piperidine ring, a benzoyl lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom, a piperidinyl group which may have a lower alkyl group on the piperidine ring, a 1,2,3,4-tetrahydroquinolyl lower alkyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring, a 1,2,3,4-tetrahydroquinolyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring, a 1,3,4-oxadiazolyl lower alkyl group which may have an oxo group as a substituent on the 1,3,4-oxadiazole ring, a 1,3,4-oxadiazolyl group which may have an oxo group as a substituent on the 1,3,4-oxadiazole ring, a cycloalkyl lower alkyl group, a cycloalkyl group, a thienyl lower alkyl group, a thienyl group, a lower alkoxy lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, an imidazolyl lower alkyl group, or an imidazolyl group; and R^(B) and R⁵², together with carbon atoms to which they bind, may form a cycloalkyl group or a tetrahydro-4H-pyranyl group; provided that the alkyl moiety of the R⁵²(R^(B))CH— group in the compound (1aaa) has not more than six carbon atoms.

The reaction of the compound (35′) with the compound (39) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (35′) with the compound (40) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (35′) with the compound (41) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

When the reaction is carried out using the compound (41) as a starting material, wherein R³ and R⁵² together with carbon atoms bound to them form a cycloalkyl ring or a tetrahydro-4H-pyran ring using a hydride reducing agent, a cycloalkyloxytrialkylsilane such as [(1-ethoxycyclopropyl)oxy]trimethylsilane may be used as a starting material in place of the compound (41) to generate the above described compound (41) in the reaction system.

The reaction of the compound (35′) with the compound (42) is carried out under the condition to similar that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (35′) may also be produced from the compound (1yy), (1zz) or (1aaa) under the reaction condition similar to that of the reaction which converts the compound (1iii′) into the compound (1hhh′) of the later described reaction formula 24.

In the formula, R¹, R², X₁, Y, T, l, A₁₄₀ and X₂ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively;

R^(14g) and R^(15f) are a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one tertiary amine thereon substituted with a lower alkoxycarbonyl group; and R^(14h) and R^(15g) are a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one secondary amine thereon.

The reaction which converts the compound (1ccc) into the compound (1ddd) may be carried out under the reaction condition similar to that of the hydrolysis B described for the above described reaction formula 9.

In the formula, R^(74a) represents a nitro group or a —R¹ group, and R¹, R², X₁, Y, T, l and A₁₀ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively;

R^(14i) and R^(15h) are a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one lower alkoxycarbonyl lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonyl lower alkyl group, or —(B₁₂CO)t-N(R^(20a))R^(51′) group thereon; R^(14j) and R^(15i) are a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one carboxy lower alkoxy group, carboxy group, carboxy lower alkyl group, or —(B₁₂CO) t-N(R^(20a))R^(52′) group thereon; B₁₂ and t are the same as described above; R^(20a) represents a hydrogen atom, a cycloalkyl group, an amino group which have a lower alkoxycarbonyl group as a substituent, a benzoyl group which may have 1 to 3 alkoxy groups as substituents on the phenyl ring, a lower alkyl group, a lower alkyl group which has 1 or 2 phenyls which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of an lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkylthio group, a phenyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a lower alkoxy group which may have a halogen atom as a substituent and a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a cycl alkyl lower alkyl group, a pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, an amino substituted lower alkyl group which may have a substituent selected from the group consisting of a phenyl group and a lower alkyl group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a naphthyl lower alkyl group, a pyridyl lower alkyl group, a quinolyl lower alkyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group, a phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group, a phenyl lower alkanoyl group, a lower alkanoyl group which may have a halogen atom as a substituent, an imidazolyl lower alkanoyl group, a lower alkoxycarbonyl lower alkyl group, a pyridyl group, or a carboxy lower alkyl group; R^(51′) is a lower alkoxycarbonyl group or a lower alkoxycarbonyl lower alkyl group; R^(52′) is a hydrogen atom or a carboxy lower alkyl group; and R⁵³ is a lower alkyl group.

The reaction which converts the compound (1eee) into the compound (1fff) may be carried out under the reaction condition similar to that of the hydrolysis B as described in the above described reaction formula 9.

Any of the reaction conditions for typical esterification reaction may be used for the reaction of the compound (1fff) with the compound (43). For example, the above described reaction is carried out in the presence of a mineral acid such as hydrochloric acid or sulfuric acid, and a halogenation agent such as thionylchloride, phosphorus oxychloride, phosphorus pentachloride, or phosphorus trichloride. The compound (43) is used in large excess over the compound (1fff). The above described reaction favorably proceeds at typically about 0 to 150° C., preferably about 50 to 100° C., and is completed in general in about 1 to 10 hours. The esterification described above may be carried out using a condensation agent such as carbodiimide in the presence of a basic compound such as dimethylaminopyridine. A typical reaction condition for generating an amide bond, which is used in the reaction of the compound (1b) with the compound (6) in the reaction formula 2, may also be used.

The reaction of the compound (1fff) with compound (43) may also be carried out in the presence of the same basic compound and the solvent as those used in the reaction of the compound (2) with the compound (3) of the reaction formula 1. The reaction is carried out at typically about 0 to 100° C., and preferably about 0 to 70° C., and is completed in general in about 1 to 30 hours.

The compound (1eee) may also be produced using a halogenated lower alkyl such as methyl iodide in place of the compound (43) under the condition similar to that of the reaction of the compound (2) with the compound (3) of the reaction formula 1.

In the formula, R¹, R², X₁, Y, A₁₀, R^(13a), B₂₁ and R⁵³ are the same as described above, and R⁵⁴ is a lower alkyl group, provided that the a and b of A₁₀ are bound to Y and the piperidinyl group, respectively.

The reaction which converts the compound (1ggg-1) into the compound (1v-1) and the reaction which converts the compound (1ggg-2) into the compound (1v-2) may be carried out under the reaction condition similar to that of the hydrolysis B described for the above described reaction formula -9, respectively.

The reaction of the compound (1v-1) with the compound (43) and the reaction of the compound (1v-2) with the compound (43) is carried out under the reaction condition similar to that of the reaction of the compound (1fff) with the compound (43) of the above described reaction formula 20.

The compound (1ggg-1) may also be produced using a halogenated lower alkyl such as methyl iodide in place of the compound (43) under the condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

Similarly, the compound (1ggg-2) may also be produced using a halogenated lower alkyl such as methyl iodide in place of the compound (43) under the condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

In the formula, R¹, R², X₁, Y, T, l and A₁₀ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively;

R^(14k) and R^(15j) are a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one —B₂₁CONHNH₂ group, wherein B²¹ is the same as described above, thereon; and R^(14l) and R^(15k) are a 5- to 10-membered saturated or unsaturated heterocyclic ring the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one group of the formula:

thereon.

The reaction which converts the compound (1hhh) into compound (1iii) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, R¹, R², X₁, Y, A₁₀, B₂₁ and X₂ are the same as described above, the a and b of A₁₀ are bound to Y and (T)l, respectively, R⁵⁵ is a lower alkanoyl group, and R^(55a) is a lower alkyl group.

The reaction of the compound (44) with the compound (45) is carried out under the condition to similar that of the reaction which converts the compound (1f) into the compound (1h) of the above described reaction formula 3.

The reaction of the compound (44a) with the compound (46) is carried out under the condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction which converts the compound (47) into the compound (1rrr) is carried out under the condition similar to that of the reaction which converts the compound (1f) into the compound (1h) of the above described reaction formula 3.

In the formula, R¹, R², X₁, Y, T, l, A₁₀ and X₂ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively;

R^(14m) and R^(15l) are a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one hydroxyl group or hydroxyl group substituted lower alkyl group thereon; R^(14n) and R^(15m) are a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one —OR⁵⁶ group thereon; R⁵⁶ represents a phenyl group which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a cyano group, a lower alkyl group which may have a halogen atom as a substituent, and a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkyl group which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, and a lower alkoxy group which may have a halogen atom as a substituent, a pyridyl lower alkyl group, a lower alkyl group, a lower alkoxy lower alkyl group, a benzoyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group; or a —B₁₅—CO—NR²⁶R²⁷ group, wherein B₁₅, R²⁶ and R²⁷ are the same as described above, provided that, the R⁵⁶ of the compound (48), which reacts with the above described heterocyclic group substituted with at least one hydroxyl group substituted lower alkyl group of the compound (1hhh′), is an unsubstituted phenyl group or a lower alkyl group.

The reaction of the compound (1hhh′) with the compound (48) is carried out under the condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction which converts the compound (1iii′) into the compound (1hhh′) may be carried out under the condition to similar that of the hydrolysis B described in the above described reaction formula 9.

The compound (1iii′) may be converted into the compound (1hhh′) by a reduction reaction. This reduction reaction is, for example, carried out in an appropriate solvent in the presence of a catalytic hydrogen reducing agent.

Examples of the solvent used include water, fatty acids such as acetic acid, alcohols such as methanol, ethanol, and isopropanol, aliphatic hydrocarbons such as hexane and cyclohexane, ethers such as dioxane, tetrahydrofuran, diethyl ether, monoglyme, and diglyme, esters such as ethyl acetate and methyl acetate, aprotic polar solvents such as N,N-dimethylformamide, and a mixture thereof.

Examples of the catalytic hydrogen reducing agent used include palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. These reducing agents may be used singly or as a mixture of two or more.

The catalytic hydrogen reducing agent is favorably used generally in an amount of 0.02 to 1 time of the compound (1iii′) on a weight basis.

The reaction temperature is typically at about −20 to 100° C., and preferably at about 0 to about 80° C. The reaction is preferably carried out at a hydrogen pressure of typically 1-10 atm, and is completed in general in about 0.5 to 20 hours.

In the formula R¹, R², X₁, Y, T, l, A₁₀, R^(A) and X₂ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively;

R^(14o) and R^(15n) are a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹¹ and R¹⁵, except that the heterocyclic group has at least one —(B₁₂CO) tNHR^(20a) group thereon; R^(14p) and R^(15o) are a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one —(B₁₂CO) tN(R^(20a))R^(21b) group thereon; and R^(14q) and R^(15p) are a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic group has at least one —(B₁₂CO)tN(R^(20a))R^(21c) group thereon; R^(14r) and R^(15q) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵ except that the heterocyclic ring has at least one —(B₁₂CO)tN(R^(20a))(CHR^(A)R^(21d)) group thereon, wherein B₁₂, t and R^(20a) are the same as described above; R^(21b) represents a lower alkyl group, a cycloalkyl group, a lower alkyl group which have 1 or 2 phenyls which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent and a lower alkylthio group, a phenyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a lower alkoxy group which may have a halogen atom as a substituent and a lower alkyl group which may have a halogen atom as a substituent, a cycloalkyl lower alkyl group, a pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, an amino substituted lower alkyl group which may have a substituent selected from the group consisting of a phenyl group and a lower alkyl group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a naphthyl lower alkyl group, a pyridyl lower alkyl group, a quinolyl lower alkyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group, a phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group, a lower alkoxycarbonyl lower alkyl group, a pyridyl group, or a carboxy lower alkyl group; R^(21c) represents a benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring, a lower alkoxycarbonyl group, a phenyl lower alkanoyl group, a lower alkanoyl group which may have a halogen atom as a substituent or an imidazolyl lower alkanoyl group; and R^(21d) represents a hydrogen atom, a lower alkyl group, a lower alkyl group which have 1 or 2 phenyl groups which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent and a lower alkylthio group, a phenyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may be substituted with a halogen atom, a lower alkoxy group which may be substituted with a halogen atom and a lower alkylthio group, a cycloalkyl lower alkyl group, a cycloalkyl group, a pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, a pyrrolidinyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, an amino substituted lower alkyl group which may have a group selected from the group consisting of a phenyl group and a lower alkyl group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a 1,2,3,4-tetrahydronaphthyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a naphthyl lower alkyl group, a naphthyl group, a pyridyl lower alkyl group, a pyridyl group, a quinolyl lower alkyl group, a quinolyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,3,4-tetrazolyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,4-triazolyl group, a tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group, a tetrahydrofuryl group which may have a hydroxyl group as a substituent on the lower alkyl group, a phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group, a lower alkoxycarbonyl lower alkyl group or a carboxy lower alkyl group; provided that the alkyl moiety of CHR^(A)R^(21d) in the side chain (—(B₂₁CO)tN(R^(20a))(CHR^(A)R^(21d))) has not more than 6 carbon atoms.

The reaction of the compound (1uuu) with the compound (49) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1uuu) with the compound (51) is carried out under reaction conditions similar to those of the reaction of the compound (1b) and the compound (5) of the above described reaction formula 2.

The reaction of the compound (1uuu) with the compound (50) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, R¹, R², X₁, Y, T, l, and A₁₀ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively;

R^(14s) and R^(15r) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —(CO)oB₁₃X₂ group thereon; R^(14t) and R^(15s) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —(CO)oB₁₃R⁸⁴ group thereon; and R⁸⁴ is an —NR²²R²³ group or an imidazolyl group; wherein B₁₃, o, X₂, R²² and R²³ are the same as described above.

The reaction of the compound (1yyy) with the compound (52) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

In the formula, R¹, R², X₁, Y, T, l, and A₁₀ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively;

R^(14s′) and R^(15r′) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —N(R²⁸)—CO—B₁₆X₂ group thereon; and R^(14u) and R^(15t) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —N(R²⁸)—CO—B₁₆NR²⁹R³⁰ group thereon; wherein R²⁸, B₁₆, X₂, R²⁹ and R³⁰ represent the same as described above.

The reaction of the compound (1aaaa) with the compound (53) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

In the formula, R^(74a), R², X₁, Y, T, l, and A₁₀ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively; R^(14v) and R^(15u) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —B₁₂COOH group thereon; and

R^(14w) and R^(15v) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —B₁₂CONR²⁰R²¹ group thereon; wherein B₁₂, R²⁰ and R²¹ are the same as described above.

The reaction of the compound (1cccc) with the compound (54) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, R¹, R², X₁, Y, T, l, and A₁₀ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively; R^(14x) and R^(15w) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —O—B₁₅COOH group thereon; and

R^(14y) and R^(15x) represent a 5- to 10-membered saturated or unsaturated heterocyclic group as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —O—B₁₅CONR²⁶R²⁷ group thereon; wherein B₁₅, R²⁶ and R²⁷ are the same as described above.

The reaction of the compound (1eeee) with the compound (55) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively;

R^(14z) and R^(15y) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —N(R³¹)—B₁₇—COOH group thereon; and R^(14aa) and R^(15z) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —N(R³¹)—B₁₇CONR³²R³³ group thereon; wherein R³¹, B₁₇, and R³², R³³ are the same as described above.

The reaction of the compound (1gggg) with the compound (56) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, R¹, R², X₁, Y, T, l, and A₁₀ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively; R^(14bb) and R^(15aa) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —COOH group thereon; and

R^(14cc) and R^(15bb) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —CONR²⁶R²⁷ group thereon; wherein R²⁶ and R²⁷ are the same as described above.

The reaction of the compound (1iiii) with the compound (57) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, R¹, R², X₁, Y, T, l, R^(14a) and A₁₀ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively;

h represents 0 or 1; and R⁵⁷ represents a lower alkoxycarbonyl group.

The reaction which converts the compound (1kkkk) into the compound (1llll) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

In the formula, R¹, R², X₁, R³, R⁴, Y, R^(H) and R¹² are the same as described above, R⁵⁸ represents a lower alkyl group, and g represents 0 or 1.

The reaction which converts the compound (1mmmm) into the compound (1nnnn) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The reaction of the compound (1nnnn) with the compound (58) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, R¹, R², X₁, Y, T, l, A₁₀ and X₂ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively; R^(14hh) and R^(15gg) represent 5- to -10 membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —(CO)o-B₁₃NH(R^(22a)) group thereon;

R^(14ii) and R^(15hh) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —(CO)o-B N(R^(22a))R^(23a) group thereon; R^(14jj) and R^(15ii) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —(CO)o-B₁₃N(R^(22a))R^(23b) group thereon; R^(14kk) and R^(15jj) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —(CO)o-B₁₃N(R^(22a))(CHR^(A)R^(23c)) group thereon, wherein R^(A), B₁₃ and o are the same as described above; R^(22a) is a hydrogen atom, a lower alkyl group, a benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring, a phenoxy lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group or a phenyl group; R^(23a) represents a lower alkyl group, a phenoxy lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group or a phenyl group; R^(23b) represents a benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring; and R^(23c) represents a hydrogen atom, a lower alkyl group, a phenoxy lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group or a phenyl group; provided that the alkyl moiety of the —CHR^(A)R^(23c) group in the side chain (—(CO)o-B₁₃—N(R^(22a))(CHR^(A)R^(23c))) of the compound (1ssss) has not more than 6 carbon atoms.

The reaction of the compound (1pppp) with the compound (59) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1pppp) with the compound (61) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction of the compound (1pppp) with the compound (60) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, R¹, R², X₁, Y, T, l, A₁₀ and X₂ are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively; R^(14ll) and R^(15kk) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —(O—B₁₅)s-CONH(R^(26a)) group thereon;

R^(14mm) and R^(15ll) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —(O—B₁₅)s-CON(R^(26a))(R^(27a)) group thereon; R^(14nn) and R^(15mm) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —(O—B₁₅)s-CON(R^(26a))(CHR^(A)R^(27b)) group, wherein B₁₅, s and R^(A) are the same as described above; R^(26a) represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group or an imidazolyl lower alkyl group; R^(27a) represents a lower alkyl group, a phenyl lower alkyl group or an imidazolyl lower alkyl group; and R^(27b) represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a phenyl group, an imidazolyl group or an imidazolyl lower alkyl group; provided that the alkyl moiety of the —CHR^(A)R^(27b) group in the side chain (—(O—B₁₅)s-CO(R^(26a))(CHR^(A)R^(27b))) of the compound (1vvvv) has not more than 6 carbon atoms.

The reaction of the compound (1tttt) with the compound (62) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1tttt) with the compound (63) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R¹, R², X₁, Y, T, l, A₁₀, R^(14v), R^(15u), R^(14k) and R^(14j) are the same as described above, provided that the a and b of A₁₀ are bound to Y and (T)l, respectively;

R⁵⁹ represents a lower alkyl group; and R^(14oo) and R^(15nn) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —B₂₁CONHNHCOOR⁵⁹ group, wherein B₂₁ is the same as described above.

The reaction of the compound (1cccc′) with the compound (102) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction which converts the compound (1yyyy) into the compound (1hhh) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The compound of the present invention of the general formula (1) having various R¹s is produced, for example, as shown by the following reaction formulas 37 to 46.

In the formula, R², X₁, Y, A₁₆, R⁶, R⁸, B₂₁, R^(A) and X₂ are the same as described above, provided that the B₂₁CHR^(A) moiety of the (R⁶—B₂₁CHR^(A)—) group of the compound (1y) has not more than 6 carbon atoms.

The reaction of the compound (19) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (19) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction of the compound (19) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, R², X₁, Y, A, R⁶, B, R^(A) and X₂ are the same as described above, R^(8a) represents a lower alkyl group which may have a lower alkoxy group as a substituent, a lower alkylsulfonyl group or a phenyl lower alkyl group, R^(8b) represents a hydrogen atom, a phenyl group, phenyl lower alkyl group or a lower alkyl group which may have a lower alkoxy group as a substituent, and R^(8c) represents a lower alkanoyl group, provided that the alkyl moiety of the —CHR^(A)R^(8b) group of the compound (1cc) has not more than 6 carbon atoms.

The reaction of the compound (1aa) with the compound (23) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1aa) with the compound (24) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction of the compound (1aa) with the compound (25) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, R², X₁, Y, A, B₂₁, f, R^(A) and R⁶ are the same as described above, provided that the (B₂₁)fCHR^(A) moiety of the (—(B₂₁)fCHR^(A)NHR⁶) group of the compound (1ee) has not more than 6 carbon atoms.

The reaction of the compound (26) with the compound (27) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R⁸⁶ represents a —Y-A group or a halogen atom, and R², X₁, Y, A, and R⁶, are the same as described above.

The reaction of the compound (28) with the compound (27) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, R², X₁, Y, A, R⁶, R^(8a), R^(8b), R^(8c), R^(A) and X₂ are the same as described above, provided that the alkyl moiety of the —CHR^(A)R^(8b) group of the compound (1hh) has not more than 6 carbon atoms.

The reaction of the compound (1ff′) with the compound (23) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1ff′) with the compound (24) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction of the compound (1ff′) with the compound (25) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, R², X₁, Y, A, R⁶ and X₂ are the same as described above.

The reaction which converts the compound (30) into the compound (1jj) may be carried out under reaction conditions similar to those of the reaction which converts the compound (1f) into the compound (1h) of the above described reaction formula 3.

The reaction which converts the compound (1jj) into the compound (1kk) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction of the compound (30) with the compound (32) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

In the formula, R², X₁, Y, A, X₂ and R⁶ are the same as described above, B₂₃ represents a lower alkylene group or a lower alkenylene group, and the B₂₃—HC═CH— moiety in the side chain (R⁶B₂₃—HC═CH—) in the compound (1mm) has 1 to 3 double bonds and has not more than 6 carbon atoms.

The reaction of the compound (33) with the compound (34) is carried out in an appropriate inert solvent and in the presence of a condensation agent.

Examples of the inert solvent used in the above described reaction include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as α-dimethylaminoacetic acid and acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, 1-methyl-2-pyrrolidone, pyridine, dimethyl sulfoxide, dimethylformamide, and hexamethylphosphoric acid triamide, and a mixture thereof.

Examples of the condensation agent include palladium complexes such as bis(benzonitrile)dichloropalladium (II).

The condensation agent is appropriately used in an amount typically 0.01 to 1 times, and preferably 0.01 to 0.5 times of the compound (33) on a molar basis.

The above described reaction favorably proceeds typically at 0 to 200° C., and preferably at about room temperature to about 150° C. and is, in general, completed in about 10 minutes to 20 hours.

The above described reaction proceeds advantageously by adding a alkali metal salt of fatty acid such as sodium acetate to the reaction system.

In the formula, R², X₁, Y, A and R⁶ are the same as described above.

The reaction which converts the compound (1nn) into the compound (1oo) may be carried out under reaction conditions similar to those of the reaction which converts the compound (1f) into the compound (1g) of the above described reaction formula 3.

In the formula, A₁₇ represents a group of the formula:

wherein R², R³, p, X₁, Y, A, Bo and R⁶ are the same as described above.

The reaction of the compound (64) with the compound (65) is carried out in an appropriate solvent in the presence of a condensation agent.

Any of the solvents, which are used in the reaction of carboxylic acid halide with amine (1b) by the method (d) of the formula 2 for reacting the compound (1b) with the compound (6) (reaction which Produces an amide bond); may be used in this reaction.

Examples of the condensation agent used include a mixture of an azocarboxylate (such as diethyl azodicarboxylate) with a phosphorus compound (such as triphenylphosphine).

The condensation agent is appropriately used in an amount typically at least equimolar to the compound (64), and preferably 1 to 2 times of the compound (64) on a molar basis.

The compound (65) is appropriately used in an amount typically at least equimolar to the compound (64), and preferably 1 to 2 times of the compound (64) on a molar basis.

The above described reaction favorably proceeds typically at 0 to 200° C., preferably at around 0 to 150° C. and is, in general, completed in around 1 to 10 hours.

In the formula, R², X₁, Y, A, and R⁶ are the same as described above.

The reaction of the Compound (30) with the compound (66) is carried out in the presence or absence of a basic compound, and preferably in the absence of the basic compound in an appropriate solvent or without a solvent.

Any of the inert solvents and the basic compounds, which are used in the reaction of carboxylic acid halide with amine (1b) by the method (d) of the formula 2 for reacting the compound (1b) with the compound (6) (reaction which produces an amide bond), may be used in this reaction.

The compound (66) may be used in an amount typically at least about 1 to 5 times, and preferably about 1 to 3 times of the compound (30) on a molar basis.

The above described reaction is carried out typically at 0 to 200° C., and preferably at around room temperature to 150° C. and is, in general, completed in around 5 minutes to 50 hours.

A boron compound such as a boron trifluoride-diethyl ether complex may be added to the system of the above described reaction.

In the formula, R², X₁, Y, T₂, A₁₀, R¹⁴, R¹⁵, B₂₁, R^(A), X₂, R⁶ and R⁵⁹ are the same as described above, provided that the a and b of A₁₀ are bound to Y and T₂, respectively.

The reaction which converts the compound (68) into the compound (71) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The reaction of the compound (71) with the compound (100) is carried out under reaction conditions similar to those of the reaction of the compound (1fff) with the compound (43) in formula 20 as described above.

The compound (68) may also be produced using a halogenated lower alkyl group such as methyl iodide in place of the compound (100) in a reaction similar to the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction which converts the compound (68) into the compound (69) may be carried out, for example, (1) by reducing the compound (68) with a catalytic hydride reducing agent in an appropriate solvent, or (2) by reducing the compound (68) with a reducing agent such as a mixture of a metal or a metal salt with an acid, or a mixture of a metal or a metal salt with an alkali metal hydroxide, a sulfide, an ammonium salt or the like, in an appropriate inert solvent.

Examples of the solvent in using the method (1) include water, acetic acid, alcohols such as methanol, ethanol, and isopropanol, hydrocarbons such as n-hexane and cyclohexane, ethers such as dioxane, tetrahydrofuran, diethyl ether, and diethylene glycol dimethyl ether, esters such as ethyl acetate and methyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, and a mixture thereof. Examples of the catalytic hydride reducing agent used include palladium, palladium black, palladium-carbon, platinum-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. These reducing agents may be used singly or in a mixture of two or more. In general, the reducing agent may be used in an amount 0.02 to 1 times of the compound (68) on a weight basis. The reaction temperature is typically about −20 to 150° C., and preferably about 0 to 100° C., and the hydrogen pressure is typically at 1 to 10 atm. In general, the above described reaction is completed in about 0.5 to 100 hours. An acid such as hydrochloric acid may be added to the above described reaction system.

The reducing agent which may be used in using the method (2) is a mixture of iron, zinc, tin or stannous chloride with a mineral acid such as hydrochloric acid or sulfuric acid; or a mixture of iron, ferrous sulfate, zinc or tin with an alkali metal hydroxide such as sodium hydroxide, a sulfate such as ammonium sulfate or an ammonium salt such as ammonium hydroxide or ammonium chloride. Examples of the inert solvent include water, acetic acid, alcohols such as methanol and ethanol, and ethers such as dioxane, and a mixture thereof. The reaction conditions may be chosen appropriately depending on the reducing agent used. For example, when stannous chloride or hydrochloric acid is used as the reducing agent, the reaction is appropriately carried out advantageously at about 0 to 150° C., and for around 0.5 to 10 hours. The above described reducing agent is used in an amount at least equal molar to the compound (68), and typically 1 to 5 times of the compound (68) on a molar basis.

The reaction of the compound (69) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (69) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (69) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction which converts the compound (69) into the compound (37a), the reaction which converts the compound (70a) into the compound (37d), the reaction which converts the compound (70b) into the compound (37c) and the reaction which converts the compound (70c) into the compound (37b) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The reaction of the compound (71) with the compound (36) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (69) with the compound (32) is carried out under reaction conditions similar to those of the reaction of the compound (30) with the compound (32) in the reaction formula 42 as described above.

In the formula, R², X₁, Y, A₁₀, B₃, R¹⁴, R¹⁵, R^(A), R^(74a) and X₂ are the same as described above;

R^(c) represents a —CONR¹⁴R¹⁵ group or —COOR^(59b) group, R^(59b) represents a lower alkyl group or a phenyl lower alkyl group; R^(17a) represents a lower alkyl group, a cycloalkyl group, a lower alkyl sulfonyl group or a lower alkenyl group; R^(17b) represents a hydrogen atom or a lower alkyl group; and R^(17c) represents a cycloalkylcarbonyl group, a lower alkanoyl group which may have a halogen atom as a substituent or an amino substituted lower alkanoyl group which may have a lower alkyl group as a substituent; wherein the a of A₁₀ is bound to the Y group and the b is bound to an —NHB₃—Rc group, —N(R^(17a))B₃-Rc group, —N(CH(R^(A))(R^(17b)))B₃-Rc group or —N(R^(17c)) B₃—Rc group.

The reaction of the compound (72a) with the compound (73) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (72a) with the compound (75) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (72a) with the compound (74) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², X₁, Y, A₁₀, B₃, R¹⁴ and R¹⁵ are the same as described above, R^(17d) represents a lower alkanoyl group which is substituted with a halogen atom, R⁶⁰ represents an amino group which may be substituted with a lower alkyl group, and R⁶¹ represents an amino substituted lower alkanoyl group which may be substituted with a lower alkyl group, wherein the a A₁₀ is bound to the Y group and the b is bound to an N(R^(17d))B₃—CONR¹⁴R¹⁵ group or —NR⁶¹B₃—CONR¹⁴R¹⁵ group.

The reaction of the compound (72e) with the compound (76) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) in the reaction formula 1 as described above.

In the formula, R², X₁, Y, R⁶, B₂₁, R^(A) and X₂ are the same as described above, and A₁₁ represents a group of the formula:

wherein R³ and p are the same as described above, provided that the alkyl moiety in the side chain (—NHCH(R^(A))(B₂₁R⁶) group) of the compound (78b) has not more than 6 carbon atoms.

The reaction which converts the compound (77a) into the compound (77b) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (77b) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (77b) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (77b) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R¹, R², X₁, Y and A₁₁ are the same as described above, and i represents an integer of 2 to 4.

In general, the reaction of the compound (77c) with the compound (79) is called Friedel-Crafts reaction and is carried out in an appropriate solvent in the presence of a Lewis acid.

Any of the Lewis acids typically used in the Friedel-Crafts reaction may be used here. Examples of these Lewis acids include aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, and concentrated sulfuric acid. These Lewis acids are used singly or in a mixture of two or more. The Lewis acid is used typically in an amount 2 to 6 times of the compound (77c) on a molar basis.

Examples of the solvent used here include aromatic hydrocarbons such as carbon disulfide, nitrobenzene, and chlorobenzene, and halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon tetrachloride, and tetrachloroethane, and a mixture thereof.

The compound (79) is typically used in an amount at least equimolar to the compound (77c), and preferably 1 to 5 times of the compound (77c) on a molar basis.

Typically the above described reaction proceeds favorably at 0 to 120° C., and preferably about 0 to 70° C., and is generally completed in about 0.5 to 24 hours.

In the formula, R², X₁, Y, R⁶, X₂, B₂₁ and R^(A) are the same as described above. A₁₂ represents a group of the formula:

R³ and p are the same as defined above, and R⁶² represents a lower alkanoyl group or a hydroxyl group substituted lower alkyl group, provided that the alkyl moiety in the side chain (NHCH(R^(A))(B₂₁R⁶) group) of the compound (81b) has not more than 6 carbon atoms.

The reaction which converts the compound (80a) into the compound (80b) is carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (80b) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (80b) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (80b) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R¹, R², X₁, and Y are the same as above,

A₁₃ represents a group of the formula:

wherein R³ and p are the same as described above, and R^(63a) represents a lower alkanoyl group or a lower alkyl group, and A₁₄ represents a group of the formula:

wherein R^(63b) represents a lower alkanoyl group which is substituted with a halogen atom at the α-position or a lower alkyl group which is substituted with a halogen atom at the 2 position.

The reaction which converts the compound (80b′) into the compound (35a) is carried out in the presence of a halogenating agent in an appropriate solvent.

Examples of the halogenating agent include halogen atoms such as bromine and chlorine, iodine chloride, sulfuryl chloride, copper compounds such as cupric bromide, and N-halogenated succinic acid imides such as N-bromosuccinic acid imide and N-chlorosuccinic acid imide.

Examples of the solvent used include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, fatty acids such as acetic acid and propionic acid, and carbon disulfide.

The halogenated agent is appropriately used in an amount typically 1 to 10 times, and preferably 1 to 5 times of the compound (80b′) on a molar basis.

The above described reaction is carried out typically at 0° C. to the boiling point of the solvent, and preferably at about 0 to 100° C., and is completed typically in about 5 minutes to 30 hours.

When an N-halogenated succinic acid imide is used as a halogenated agent, a peroxide such as benzoyl peroxide may be added to the reaction system as a initiator for the radical reaction.

In the formula, R², X₁, Y, A₁₀, T₂, R⁵⁹, R^(8a), R^(8b), R^(8c), X₂ and R^(A) are the same as described above, and

R⁶⁴ represents a phenyl lower alkoxycarbonyl group, provided that the alkyl moieties in the side chain (—N(CHR^(A)R^(8b))(R⁶⁴) group) of the compound (84b) and the side chain (—NH(CHR^(A)R^(8b)) group) of the compound (84e) have not more than 6 carbon atoms, respectively, and the a and b of A₁₀ are bound to the Y group and the T₂ group, respectively.

The reaction of the compound (83) with the compound (23) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (69) with the compound (82), and the reaction of the compound (83) with the compound (25) are carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (83) with the compound (24) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reactions which respectively convert the compound (84a) into the compound (84d), the compound (84b) into the compound (84e), and the compound (84c) into the compound (84f) are carried out under reaction conditions similar to those of the reaction which converts the compound (1iii′) into the compound (1hhh′) by reduction as described for the above described reaction formula 24.

In the formula, R², X₁, Y, A₁₀, B₂₁, R^(74a) and X₂ are the same as described above, provided that the a and b of A₁₀ are bound to the Y group and the B₂₁ group, respectively.

The reaction which converts the compound (85) into the compound (7′) is carried out by reacting compound (85) to a halogenating agent in an appropriate solvent or without solvent.

Examples of the halogenating agent include mineral acids such as hydrochloric acid and hydrobromic acid, N,N-diethyl-1,2,2-trichlorovinyl azide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, sulfonyl halide compounds such as thionyl chloride, mesyl chloride, and tosyl chloride, and a mixture of carbon tetra bromide with triphenylphosphine. The sulfonyl halide compound is used together with a basic compound.

Any of the basic compounds used in the reaction of the compound (2) with the compound (3) of the reaction formula 1 may be used.

Examples of the solvent used include ethers such as dioxane, tetrahydrofuran, and diethyl ether, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, and dimethylformamide, and a mixture thereof.

When a sulfonyl halide compound is used together with a basic compound as a halogenating agent, the sulfonyl halide compound is appropriately used in an amount typically at least equimolar to the compound (85), and preferably 1 to 2 times of the compound (85) on a molar basis. The basic compound is used typically in a catalytic amount of the compound (85), and preferably in a catalytic amount to an amount equimolar to the compound (85). When another halogenating agent is used, such a halogenating agent is used at least equimolar to the compound (85), and typically used in a large excess amount.

The above described reaction proceeds favorably typically at room temperature to 200° C., and preferably at room temperature to 150° C., and in general is completed in about 1 to 80 hours.

In the formula, R^(74a), R², X₁, Y, A₁₀ and B₂₁ are the same as described above, and R⁶⁵ represents a tri-lower alkyl silyl group, provided that the a and b of A₁₀ are bound to the Y group and the B₂₁ group, respectively.

Here, examples of the tri-lower alkyl silyl group include trialkylsilyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as

a tert-butyldimethylsilyl group, trimethylsilyl group, and diethylmethylsilyl group.

The reaction which converts the compound (86) into the compound (85) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

In the formula, R^(74a), R², X₁, Y, A₁₀, B₂₁, R⁶⁵ and X₂ are the same as described above, and R⁶⁶ represents a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group, provided that the a and b of A₁₀ are bound to Y and B₂₁, respectively, and the alkyl moieties in the side chain (—Y-A₁₀-B₂₁CH₂OH) of the compound (85a) and the side chain (—Y-A₁₀-B₂₁CH₂OR⁶⁵) of the compound (86a) have not more than 6 carbon atoms.

The reaction which converts the compound (69a) into the compound (85a) is carried out under the similar reaction conditions as the reaction which converts the compound (1f) into the compound (1g) of the above described reaction formula 3.

The reaction of the compound (85a) with the compound (101) is carried out under reaction conditions similar to those of the reaction which converts the compound (2) into the compound (3) of the above described reaction formula 1.

In the formula, R², X₁, Y, A₁₀, B₂₁, R⁶, R^(A), f, R⁴³, R⁴⁴ and X₂ are the same as described above, and B_(21′) represents a lower alkylene group, provided that the a and b of A₁₀ are bound to Y and B_(21′), respectively, and the (B_(21′)) f-CH═C moiety in the side chain (—Y-A₁₀-(B_(21′))f-CH═C(COOR⁴³)(COOR⁴⁴)) of the compound (90c) and the alkyl moiety in the side chain (—NHCH(R^(A)) (B₂₁R⁶)) of the compound (90b) have not more than 6 carbon atoms, respectively.

The reaction of the compound (87) with the compound (88) is carried out under reaction conditions similar to those of the reaction of the compound (1f) and hydroxylamine of the above described reaction formula 3.

The reaction which converts the compound (89a) into the compound (89b) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (89b) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (89b) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (89b) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², X₁, Y, A₁₀, B_(21′), R⁶⁵, R⁶, B₂₁, R^(A) and X₂ are the same as defined above, provided that the a and b of A₁₀ are bound to the Y group and the B_(21′) group, respectively, and the alkyl moiety in the side chain (—NHCH(R^(A))(B₂₁R⁶)) of the compound (91b) has not more than 6 carbon atoms.

The reaction which converts the compound (86a′) into the compound (86b) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (86b) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (86b) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (86b) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², X₁, Y, A₁₀, B₂₁, B_(21′), R⁶, R^(A) and X₂ are the same as described above, provided that the a and b of A₁₀ are bound to the Y group and the B_(21′) group, respectively, and the alkyl moiety in the side chain (—NHCH(R^(A))(B₂₁R⁶)) of the compound (44c) has not more than 6 carbon atoms.

The reaction which converts the compound (92a) into the compound (92b) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (92b) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (92b) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (92b) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², X₁, and X₂ are the same as described above, R⁶⁷ represents an -A₁₀B₂₁CN group, -A₁₀-R^(59d) group, -A₁₀-T₂-COOR⁵⁹ group or -A group, R^(59d) represents a lower alkyl group, A₁₀, B₂₁, T₂ and R^(59a) are the same as described above, and R⁶⁸ represents a nitro group or a halogen atom.

The reaction of the compound (93) with the compound (94) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

In the formula, R², R⁶⁷, and X₁ are the same as described above.

The reaction which converts the compound (95a) into the compound (95b) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

In the formula, R², X₁, Y, A₇, R⁶, B₂₁, R^(A) and X₂ are the same as described above, provided that the alkyl moiety in the side chain (—NHCH(R^(A))(B₂₁R⁶)) of the compound (13b) has not more than 6 carbon atoms.

The reaction of the compound (96) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (96) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (96) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², X₁, Y, B₂₁, f, i, R⁶, B₂₁, A₁₀, R^(A) and X₂ are the same as described above, and R^(A′) represents a hydrogen atom or a lower alkyl group, provided that the alkyl moiety in the side chain (—NHCH(R^(A))(B₂₁R⁶)) in compound (98b) has not more than 6 carbon atoms, and the a and b of A₁₀ are bound to the Y group and the (B₂₁)f group, respectively.

The reaction which converts the compound (97a) into the compound (97b) is carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (97b) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (97b) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (97b) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R¹, R², X₁, Y, A₁₀, B₂₁, f, R^(A′) and A₃ are the same as described above, provided that the a and b of A₁₀ are bound to the Y group and the (B₂₁)f group, respectively.

The reaction which converts the compound (98d) into the compound (9′) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

In the formula, R¹, R², X₁, Y, A₃, R⁵⁹, A₁₀, B₂₁ and f are the same as described above, T₃ represents a direct bond or B₇ group, and B₇ represents the same as described above, provided that The a and b of A₁₀ are bound to the Y group and the (B₂₁)f group, respectively.

The reaction of the compound (9′) with the compound (99) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², X₁, Y, A₁₀, R^(14a), R^(49a), R⁴⁹, R^(49b), T, l, R^(A) and X₂ are the same as described above, provided that the CHR^(A) moiety in the side chain (—N(R^(14a))(CHR^(A)R^(49b))) of the compound (104c) has not more than 6, the a of A₁₀ is bound to the Y group, and the b of A₁₀ is bound to a —NR^(14a)H group, —NR^(14a)R^(49a) group, —NR^(14a)R⁴⁹ group, or —NR^(14a)(CHR^(A)R^(49b)) group.

The reaction of the compound (103) with the compound (38a) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (103) with the compound (38) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (103) with the compound (38b) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², X₁, Y and A are the same as described above.

The reaction which converts the compound (105) into the compound (19a) is carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47. The compound (19a) may be used in the following reaction without isolation.

In the formula, R², X₁, Y and A₁₀ is the same as described above, R^(69a) represents a thiazolidinyl group which may have an oxo group as a substituent on the thiazolidine ring, R⁶⁹ represents a thiazolidinylidene lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, and R⁷⁰ represents a thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, provided that the a of A₁₀ are bound to the Y group and the b of A₁₀ is bound to an —R⁶⁹ group or —R⁷⁰ group.

The reaction of the compound (106a) with the compound (160) is carried out under reaction conditions similar to those of the reaction of the compound (87) with the compound (88) of the above described reaction formula 58.

The reaction which converts the compound (106) into the compound (19b) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

In the formula, R², X₁, X₂, A, Y₁, A₁₀, T₂, R⁵⁹ and R^(59a) are the same as described above, X₃ represents a halogen atom, R⁷¹ represents an —R¹ group (wherein R¹ is the same as described above), a nitro group or a lower alkoxycarbonyl group, and R⁷² represents a lower alkyl group which may be substituted with a hydroxyl group, a nitro group, an amino group which may be substituted with a lower alkanoyl group, a carboxy lower alkyl group, a —(B₂₁)fC(═O)R^(A) group (wherein B₂₁, f and R^(A) are the same as described above), a lower alkanoyl group, a lower alkoxy group or a hydrogen atom, provided that the a of A₁₀ are bound to the Y₁ group and the b of A₁₀ is bound to a -T₂ group or —R⁷² group.

The reaction of the compound (94a) with the compound (107), and the reaction of the compound (94a) with the compound (107a) are carried out in an appropriate solvent and in the presence of a catalyst.

Any of the solvents used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used in this reaction.

Examples of the catalyst to be used include various metal complexes as well as various combinations of a metal complex with ligand. Examples of the metal complex include, for instance, palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium (0) and the like. Examples of the ligand include, for instance, R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (R-BINAP), S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), RAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (RAC-BINAP), t-butylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and the like.

The above described catalyst is appropriately used in an amount typically equimolar to the compound (94a), and preferably 1 to 5 times of the compound (94a) on a molar basis.

The above described reaction is carried out typically at about 0 to 200° C., preferably at about 0 to 150° C., and, in general, is completed in around 30 minutes to 10 hours.

Addition of molecular sieves such as Molecular Sieves 3A (MS3A) or Molecular Sieves 4A (MS4A) or a phosphorus compound such as triphenylphosphine or tri(2-furyl)phosphine makes the reaction proceed advantageously.

The reaction of the compound (94a) with the compound (108), compound (3) or compound (110) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (109c), wherein R⁷¹ represents a lower alkoxycarbonyl group, may be converted into the corresponding compound (109c), wherein R⁷¹ represents a carboxy group, by hydrolyzing under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

In the formula, R¹, R², X₁, X₂, Y₁, A₁₀ and T₂ are the same as described above, and R^(59c) represents a hydrogen atom, a lower alkyl or a phenyl lower alkyl group, provided that the a and b of A₁₀ are bound to a —Y₁ group and a -T₂ group, respectively.

The reaction of the compound (2) with the compound (108′) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

In the formula, R², X₁, R^(5a), R^(5b), R^(A), R^(5c) and X₂ are the same as described above, and R^(73a) represents a -A₁₀-T₂-COOR⁵⁹ group (wherein A₁₀, T₂ and R⁵⁹ are the same as described above) or an -A group (wherein A is the same as described above), provided that the a of A₁₀ is bound to an —NH— group, NR^(5a)— group, —N(CHR^(A)R^(5b)) group or —NR^(5c)— group, and the b of A₁₀ is bound to a -T₂ group, and the alkyl moiety in the side chain (—N(R^(73a))(CHR^(A)R^(5b))) of the compound (68d) has not more than 6 carbon atoms.

The reaction of the compound (111) with the compound (4) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (111) with the compound (6) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (111) with the compound (5) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², X₁, Y, A₁₀, X₂, R¹⁷, B₃, R^(74a) and R^(c) are the same as described above, provided that the a of A₁₀ is bound to a —Y group and the b of A₁₀ is bound to an —NHR¹⁷ group or —NR¹⁷B₃R^(c) group.

The reaction of the compound (112) with the compound (113) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

In the formula, R², X₁, Y, A₁₀, T₁, l, R¹⁴, and R¹⁵ are the same as described above, provided that the a and b of A₁₀ are bound to an —Y group and a -(T₁)l group, respectively.

The reaction of the compound (114) with the compound (36) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The compound (109e), in which l is 0, may also be produced by reacting the corresponding compound (114) with the compound (36) in an appropriate solvent in the presence of a basic compound and a catalyst.

The above described reaction is carried out under reaction conditions similar to those of the reaction C described for the above described reaction formula 13.

In the formula, R², X₁, Y, R⁸, B₂₁, R⁶, A₁₀, T₂, R⁵⁹, R^(A) and X₂ are the same as described above, provided that the CHR^(A)B₂₁ moiety in the side chain (—N(R⁸)(CH(R^(A)) B₂₁R⁶)) of the compound (84i) has not more than 6 carbon atoms, and the a and b of A₁₀ are bound to a —Y group and a -T₂ group, respectively.

The reaction of the compound (84g) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (84g) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (84g) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², X₁, Y, R^(8a), R^(8b), R^(8c), B, R⁶, A₁₀, T₂, R⁵⁹, R^(A) and X₂ are the same as described above, provided that the CHR^(A) moiety in the side chain (—NB(R⁶)(CH(R^(A))^(8b))) of the compound (116b) has not more than 6 carbon atoms, and the a and b of A₁₀ are bound to a —Y group and a -T₂ group, respectively.

The reaction of the compound (115) with the compound (23) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (115) with the compound (25) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (115) with the compound (24) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², X₁, Y, A₃, R¹⁴ and R¹⁵ are the same as described above, and A₁₅ represents a group of the formula:

wherein R⁷³ represents a —(B₂₁) fCH(R^(A))(NR¹⁴R¹⁹) group, and B₂₁, f and R^(A) are the same as described above, provided that the (B₂₁)fCH(R^(A)) moiety has not more than 6 carbon atoms.

The reaction of the compound (117) with the compound (36) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², X₁, Y, A₁₀, T₂, R⁶, R^(9a) and R⁵⁹ are the same as described above, provided that the a and b of A₁₀ are bound to a —Y group and a -T₂ group, respectively.

The reaction of the compound (69′) with the compound (66) is carried out under reaction conditions similar to those of the reaction of the compound (30) with the compound (66) of the above described reaction formula 46.

In the formula, R², X₁, Y, A₁₀, T₂, R⁹⁵ and R^(59b) are the same as described above, provided that the a and b of A₁₀ are bound to a —Y group and a -T₂ group, respectively.

The reaction which converts the compound (120a) into the compound (120b) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The reaction of the compound (120b) with the compound (100′) is carried out under reaction conditions similar to those of the reaction of the compound (1fff) with the compound (43) in the reaction formula 20 described above.

The compound (120a) may also be produced using a lower alkyl halide such as methyl iodide in place of the compound (100′) under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

In the formula, R¹, R², X₁, Y, A₁₀, B₅, R^(59a) and j are the same as described above, provided that the a and b of A₁₀ are bound to a —Y group and a —S group, respectively.

The reaction which converts the compound (120c) into the compound (120d) may be carried out under reaction conditions similar to those of the reaction which converts the compound (1zzzz) into the compound (1aaaaa) in formula 4 described above.

In the formula, R², X₁, Y, A₁₀, T, l, R⁶, X₂, R^(A), B₂₁ and R^(14a) are the same as described above, and R^(49c) represents a lower alkoxycarbonyl group, provided that the a and b of A₁₀ are bound to a —Y group and a -(T)l group, respectively.

The reaction of the compound (103) with the compound (38c) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction which converts the compound (104d) into the compound (104e) is carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (104e) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (104e) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (104e) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², X₁, Y, A₃, A₁₀, B₂₁, f, R^(A) and i are the same as described above, provided that the a and b of A₁₀ are bound to a —Y group and a —(B₂₁)f group, respectively, and (B₂₁)fC(R^(A)) in the side chain of the compound (123a) has not more than 6 carbon atoms in total.

The reaction of the compound (121) with the compound (122) may be carried out in an appropriate solvent in the presence of an acid.

Any of the solvents, which are used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1, may be used in this reaction.

Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as acetic acid, trifluoroacetic acid, and sulfonic acids including p-toluenesulfonic acid. These acids may be used singly or in a mixture of two or more. The acid is appropriately used in an amount typically at least 0.01 to 5 times, and preferably 0.01 to 2 times of the compound (121) on a molar basis. The compound (122) is appropriately used in an amount typically at least equimolar to the compound (121), and preferably 1 to 10 times of the compound (121) on a molar basis.

The above described reaction is carried out typically at 0 to 200° C., and preferably at around 0 to 150° C. and, in general, is completed in around 30 minutes to 10 hours.

In the formula, R², X₁, Y and A₁₀ are the same as described above, and R^(72a) represents a lower alkoxy group, provided that the a of A₁₀ is bound to a —Y group and the b of A₁₀ is bound to a —R^(72a) group or a hydroxyl group.

The reaction which converts the compound (109f) into the compound (124) may be carried out in an appropriate solvent in the presence of an acid.

In addition to water, any solvents which are used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used in this reaction.

Examples of the acid used include mineral acids such as hydrobromic acid, hydrochloric acid, and concentrated sulfuric acid, fatty acids such as formic acid and acetic acid, organic acids such as p-toluenesulfonic acid, Lewis acids such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron trifluoride, and boron tribromide, iodides such as sodium iodide and potassium iodide, a mixture of the above described Lewis acid with the above described iodide. The acid is appropriately used in an amount typically 0.1 to 5 times, and preferably 0.5 to 3 times of the compound (109f) on a molar basis.

The above described reaction is typically carried out at 0 to 150° C., and preferably at about 0 to 100° C., and, in general, is completed in about 0.5 to 15 hours.

In the formula, R², X₁, Y, A₁₀, B₅, X₂, R¹⁴, and R¹⁵ are the same as described above, and Q₁ represents an oxygen atom or a sulfur atom, provided that the a and b of A₁₀ are bound to a —X group and a -Q₁ group, respectively.

The reaction of the compound (124a) with the compound (125) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

In the formula, R², X₁, Y, R^(14a), R^(74a), T and l are the same as described above, and R^(74b) represents a lower alkanoyl group or a lower alkoxycarbonyl group, provided that the a and b of A₁₀ are bound to a —Y group and a -(T)l group, respectively.

The reaction which converts the compound (109g) into the compound (109h) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

In the formula, R², X₁, Y, A₁₀, T₂, X₂, R^(59a), B₂₃ and R⁶ are the same as described above, provided that the a and b of A₁₀ are bound to —Y group and -T₂ group, respectively.

The reaction of the compound (126) with the compound (34) is carried out under reaction conditions similar to those of the reaction of the compound (33) with the compound (34) in formula 43 described above.

In the formula, R², X₁, Y, R^(74a) and A₁₀ are the same as described above, R^(74c) represents an amino group or an —R¹ group (wherein R¹ is the same as described above), R⁷⁵ represents a lower alkanoyl group, R⁷⁶ represents a lower alkoxycarbonyl group, R⁷⁷ and R⁷⁸ are both lower alkoxy groups, and R⁷⁹ represents a hydrogen atom or a lower alkyl group, provided that the a of A₁₀ is bound to a —Y group, and the b of A₁₀ is bound to a —R⁷⁵ group, —C(R⁷⁹)═CHR⁷⁶ group or —CH(R⁷⁹)CH₂R⁷⁶ group, and the C(R⁷⁹)═CH moiety or the CH(R⁷⁹)CH₂ moiety has not more than 6 carbon atoms.

The reaction of the compound (128) with the compound (129) is carried out in an appropriate solvent in the presence of a basic compound.

Any of the conventional solvents which do not affect the reaction may be used. Examples of such a solvent include ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, and diglyme, aromatic hydrocarbons such as benzene, toluene, and xylene, aliphatic hydrocarbons such as n-hexane, heptane, and cyclohexane, amines such as pyridine and N,N-dimethylaniline, aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric acid triamide, and alcohols such as methanol, ethanol, and isopropanol, and a mixture thereof.

Examples of the basic compound include metal sodium, metal potassium, sodium hydride, sodium amide, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, carbonates such as sodium carbonate, potassium carbonate, and sodium bicarbonate, metal alcoholates such as sodium methylate, sodium ethylate, and potassium tert-butoxide, alkyl and aryl lithiums or lithium amides such as methyl lithium, n-butyryl lithium, phenyl lithium, and lithium diisopropylamide, and organic bases such as pyridine, piperidine, quinoline, trimethylamine, diisopropylethylamine, N,N-dimethylaniline. These basic compounds are used singly or in a mixture of two or more. The basic compound is appropriately used in an amount typically 0.1 to 10 times, and preferably 0.5 to 5 times of the compound (128) on a molar basis.

The compound (129) is appropriately used in an amount typically at least equimolar to the compound (128), and preferably 1 to 5 times of the compound (128) on a molar basis.

The above described reaction is carried out typically at −80 to 150° C., and preferably at about −80 to 120° C. and, in general, is completed in about 0.5 to 40 hours.

When an organic base is used as the basic compound, the reaction proceeds advantageously by adding a lithium salt such as lithium chloride to the reaction system.

The reaction which converts the compound (130) into the compound (131) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

In the formula, R², X₁, Y, R⁶⁶ and A₁₇ are the same as described above.

The reaction which converts the compound (28′) into the compound (64a) is carried out under reaction conditions similar to those of the reaction which converts the compound (1f) into the compound (1g) of the above described reaction formula 3.

In the formula, R², X₁, Y and A are the same as described above.

The reaction which converts the compound (64b) into the compound (26a) is carried out in an appropriate solvent in the presence of an oxidizing agent.

Examples of the solvent include water, fatty acids such as formic acid, acetic acid, trifluoroacetic acid, and propionic acid, esters such as ethyl acetate and methyl acetate, alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane, tetrahydrofuran, and diethyl ether, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene, and halogenated hydrocarbons such as chloroform and dichloromethane, hexamethylphosphoric acid triamide, N,N-dimethylformamide, dimethyl sulfoxide, and pyridine, and a mixture thereof.

Examples of the oxidizing agent include peracids such as performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, and o-carboxyperbenzoic acid, hydrogen peroxide, sodium metaperidodate, dichromic acid, dichromates such as sodium dichromate and potassium dichromate, manganese dioxide, permanganic acid, permanganates such as sodium permanganate and potassium permanganate, lead salts such as lead tetraacetate, silver oxide, and a Dess-Martin reagent (Dess-Martin periodinane). These oxidizing agents are used singly or in a mixture of two or more. The oxidizing agent is used in an amount typically at least equimolar to the compound (64b), and preferably 1 to 3 times of the compound (64b) on a molar basis.

The above described reaction is carried out typically at −10 to 100° C., and preferably at about 0 to 50° C., and is completed in about 30 minutes to 24 hours.

In the formula, R², X₁, Y, A₁₀, B₁₉, R¹⁸, X₂, R¹⁴, R^(74a) and R¹⁵ are the same as described above, provided that the a and b of A₁₀ are bound to a —Y group and a —B₁₉ group, respectively.

The reactions between compound (133) with the compound (134), and compound (135) with the compound (36) are carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

In the formula, A₁₀, B₃, R^(17a), R^(17b), R^(A), R¹⁷, Y₁, R^(c) and X₂ are the same as described above, and R⁸⁰ represents a —Y₁H group or a —OR⁸¹ group, R⁸¹ represents a protective group for the hydroxyl group, provided that the CHR^(A) moiety in the side chain (—N(B₃R^(c))(CHR^(A)R^(17b))) of the compound (108c) has not more than 6 carbon atoms, the a of A₁₀ is bound to a —R⁸⁰ group, and the b is bound to an —NHB₃R^(c) group, —N(R^(17a))B₃R^(c) group, —N(CHR^(A)R^(17b))B₃R^(c) group or —N(R₁₇)B₃R^(c) group.

Here, examples of the protective group for the hydroxyl group include groups, which are previously mentioned, such as a phenyl lower alkyl group, a lower alkoxy lower alkyl group, tetrahydropyranyl group, tri lower alkysilyl group, a lower alkanoyl group, and a lower alkyl group.

The reaction of the compound (108a) with the compound (73) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (108a) with the compound (75′) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (108a) with the compound (74) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction, formula 2.

When the reaction is carried out using the compound (74) as a starting material, wherein R^(A) and R^(17b) are bound with each other, together with carbon atoms bound to these groups, to form a cycloalkyl ring, and a hydride reducing agent, a cycloalkyloxytrialkylsilane such as [1-ethoxycyclopropyl]oxy]trimethylsilane may be used as a starting material in place of the compound (74) to produce the above described compound (74) in the reaction system.

In the formula, R⁸⁰, A₁₀, R¹⁷, B₃, R^(c), X₂, and R^(59b) are the same as described above, provided that the a of A₁₀ is bound to a —R⁸⁰ group and the b is bound to a —NHR¹⁷ group, —N(R¹⁷)B₃R^(c) group or —N(R¹⁷)CH₂CH₂COOR⁵⁹ group.

The reaction of the compound (108e) with the compound (113) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (108e) with the compound (137) is carried out in an appropriate solvent in the presence of an acid.

Any of the solvents used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used in this reaction.

Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, organic acids such as acetic acid, trifluoroacetic acid, and sulfonic acids including p-toluenesulfonic acid, and Lewis acids such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, and a boron trifluoride/diethyl ether complex. These acids may be used singly or in a mixture of two or more. The acid is appropriately used in an amount typically at least 0.01 to 5 times, and preferably 0.1 to 2 times of the compound (108e) on a molar basis. The compound (137) is appropriately used in an amount typically at least equimolar to the compound (108e), and preferably 1 to 10 times of the compound (108e) on a molar basis.

The above described reaction is carried out typically at 0 to 200° C., and preferably at about 0 to 150° C., and, in general, is completed in about 30 minutes to 80 hours.

In the formula, R⁸¹ is the same as described above, R^(73b) represents a -A₁₀-T₂-COOR^(59a) or -A group, and A₁₀, T₂, R^(59A) and A are the same as described above, provided that the a of A₁₀ is bound to an —OR⁸¹ group or a hydroxyl group, and the b of A₁₀ is bound to a -T₂ group.

When R⁸¹ of the material compound (138) represents a phenyl lower alkyl group, the reaction which converts the compound (138) into the compound (139) may be carried out under reaction conditions similar to those of the reduction reaction (1) (method using a catalytic hydrogen reducing agent) which is one reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

When R⁸¹ of the material compound (138) represents a tetrahydropyranyl group or tri-lower alkylsilyl group, the reaction which converts the compound (138) into the compound (139) may be carried out under reaction conditions similar to those of the hydrolysis reaction B described for above described reaction formula 9. The reaction which converts the compound (138) into the compound (139) is favorably carried out by hydrolysis using an acid. The acid is appropriately used in an amount typically 1 to 10 times, and preferably 1 to 2 times of the compound (138) on a molar basis.

When R⁸¹ of the compound (138) represents a tri-lower alkylsilyl group, the compound (138) may be treated with a fluorine compound such as tetra-n-butyl ammonium fluoride, hydrogen fluoride or cesium fluoride.

When R⁸¹ of the material compound (138) represents a lower alkoxy lower alkyl group or a lower alkyl group, the compound (138) may be treated in an appropriate solvent in the presence of an acid. Examples of the solvent include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane, tetrahydrofuran, and diethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, and polar solvents such as acetonitrile, and a mixture thereof. Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, fatty acids such as formic acid and acetic acid, sulfonic acids such as p-toluenesulfonic acid, Lewis acids such as boron trifluoride, aluminum chloride, and boron tribromide, iodides such as sodium iodide and potassium iodide, and a mixture of the above described iodide with the above described Lewis acid. The above described reaction is carried out at typically 0 to 200° C., and preferably at about room temperature to 150° C., and, in general, is completed in about 0.5 to 25 hours.

The above described hydrolysis may also be carried out using a basic compound under reaction conditions similar to those of the hydrolysis reaction B described for the above described reaction formula 9. Here, amines such as triethylamine may be used as the basic compound in addition to the basic compounds used in the hydrolysis reaction B.

When R⁸¹ of the material compound (138) represents a lower alkanoyl group, the reaction which converts the compound (138) into the compound (139) may be carried out under reaction conditions similar to those of the hydrolysis reaction B described for the above described reaction formula 9.

When R^(73a) of the compound (138) represents a group of the formula:

a dehydration reaction takes place under the above described hydrolysis conditions, and sometimes the compound (138), wherein the corresponding R^(73a) represents a group of the formula:

may be obtained.

In the formula, R⁸⁰, A₁₀, T₂, R¹⁴ and R¹⁵ are the same as described above, provided that the a and b of A₁₀ are bound to a —R⁸⁰ group and a -T₂ group, respectively.

The reaction of the compound (140) with the compound (36) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, Y₁, A₇, R¹³ and A₉ are the same as described above.

The reaction of the compound (141) with the compound (12) is carried out under reaction conditions similar to those of the reaction of the compound (13) with the compound (12) in formula 8 described above.

In the formula, R⁸⁰, A₁₀, B₂₁ and f are the same as described above, provided that the alkyl moiety in the side chain (—(B₂₁) f-CH₂NH₂) of the compound (144) has not more than 6 carbon atoms.

The reaction which converts the compound (143) into the compound (144) may be carried out under reaction conditions similar to those of the reaction using a hydride reducing agent which is one reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R⁸⁰, A₁₀, B₁₉, X₂, R¹⁸, R¹⁴ and R¹⁵ are the same as described above, provided that the a of A₁₀ is bound to a —R⁸⁰ group and the b is bound to a —B₁₉ group.

The reaction of the compound (145) with the compound (134) is carried out under reaction conditions similar to those of the reaction of the compound (133) with the compound (134) in the reaction formula 90 described above.

The reaction of the compound (146) with the compound (36) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, A₁₀, B₁₉, R¹⁴, R¹⁵, R⁸⁰ and X₂ are the same as described above, and R^(18a) represents a lower alkyl group, provided that the a and b of A₁₀ are bound to a —R⁸⁰ group and a —B₁₉ group, respectively.

The reaction of the compound (108j) with the compound (147) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

In the formula, R², X₁, X₂, X₃ and R⁶ are the same as described above, R⁸² represents a lower alkyl group, and R⁸³ represents a lower alkoxy group.

The reaction of the compound (148) with the compound (149) is carried out in an appropriate solvent in the presence of a catalyst.

Any of the solvents used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used in this reaction.

Examples of the catalyst include magnesium. The catalyst is appropriately used in an amount typically at least equimolar to the compound (148), and preferably 1 to 5 times of the compound (148) on a molar basis.

The above described reaction is carried out typically at 0 to 200° C., preferably at about 0 to 150° C., and, in general, is completed in about 30 minutes to 10 hours.

In the formula, A₁₈ represents a -A group or -A₁₀-T₂-COOR^(59b) group, and A, A₁₀, T₂, R^(59b) and X₃ are the same as described above.

The reaction which converts the compound (150) into the compound (107′) is carried out under reaction conditions similar to those of the reaction which converts the compound (85) into the compound (7′) of the above described reaction formula 55.

In the formula, R², X₁, A₁₀, T₂ and R⁶ are the same as described above, provided that the a of A₁₀ is bound to —CO group, —CH(OH) group or —CH₂, and the b is bound to a -T₂ group.

The reaction which converts the compound (109a′) into the compound (151) may be carried out under reaction conditions similar to those of the reaction using a hydride reducing agent which is one reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction which converts the compound (151) into the compound (152) is carried out under reaction conditions similar to those of the reaction which converts the compound (08) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (152) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction which converts the compound (153) into the compound (154) may be carried out under reaction conditions similar to those of hydrolysis B reaction described for the above described reaction formula 9.

In the formula, R¹, R², X₁, Y, A₁₀, B₆, B₇ or R⁵⁹ are the same as described above, and R^(19a) represents a lower alkanoyl group, provided that the a and b of A₁₀ are bound to a —Y group and a —B₆ group, respectively.

The reaction of the compound (155) with the compound (156) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, R⁸⁰, A₁₀, X₂, R¹⁴ and R¹⁵ are the same as described above.

The reaction of the compound (158) with the compound (36) is carried out under similar reacting conditions as the reaction of the compound (114) with the compound (36) of the above described reaction formula 74 in which l is 0.

In the formula, R¹, R², Y, A₁₀, R^(14a), h, T, l, R⁸, X₁ and X₂ are the same as described above, R^(85a) represents a benzoyl group, R^(85b) represents a lower alkoxy carbonyl group, a phenyl lower alkyl group, a lower alkyl group or furyl lower alkyl group, and R^(85c) represents a hydrogen atom, a lower alkyl group, a phenyl group, phenyl lower alkyl group, a furyl group or a furyl lower alkyl group, provided that the CH(R^(B))R^(85c) group of the compound (1bbbbb) has not more than 6 carbon atoms.

The reaction of the compound (1yyyy′) with the compound (160′) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (1yyyy′) with the compound (161) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1yyyy′) with the compound (162) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the formula, R², B₀, Y, X₁, A₁₇, R⁸, X₂, X₃ and R⁶ are the same as described above, R⁸⁶ represents a lower alkylsulfonyl group, and R⁸⁷ represents a oxygen atom or a —N(R⁸)— group.

The reaction of the compound (165) with the compound (163) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction which converts the compound (165) into the compound (167) is carried out under reaction conditions similar to those of the reaction which converts the compound (85) into the compound (7′) of the above described formula 55.

The reaction of the compound (166) or the compound (167) with the compound (164) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) the above described reaction formula 1.

In the formula, R⁸⁰ and A₁₀ are the same as described above, R^(15′) represents the same group as (5) in R¹⁵ described above.

The reaction of the compound (168) with the compound (170) is carried out under reaction conditions similar to those of the reaction of the compound (30) with the compound (66) of the above described reaction formula 46.

In the formula, R⁸⁰, A₁₀, T, l, R^(14bb), R^(15aa), R^(14cc), R^(15bbb), R²⁶ and R²⁷ are the same as described above.

The reaction of the compound (171) with the compound (57) is carried out under reaction conditions similar to those of the reaction of the compound (1iiii) with the compound (57) of the above described reaction formula 31.

In the formula, R¹, R², X₁, Y, A₁₀, R^(15′) and X₂ are the same as described above, and R⁸⁹ represents a lower alkyl group.

The reaction of the compound (173) with the compound (170) is carried out under reaction conditions similar to those of the reaction of the compound (30) with the compound (66) of the above described reaction formula 46.

The reaction of the compound (1ddddd) with the compound (173) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

In the formula, R¹, R², X₁, Y, X₂, B₃, R¹⁴ and R¹⁵ are the same as described above, and A₁₉ represents a group of the formula:

and A₂₀ represents a group of the formula:

wherein R³, p, B₃, R¹⁴ and R¹⁵ are the same as described above.

The reaction of the compound (174) with the compound (175) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

In the formula, R¹, R², X₁ and Y are the same as described above, A₂₁ represents a group of the formula:

and A₂₂ represents a group of the formula:

wherein R³, p, R¹⁷, B₃, R¹⁴ and R¹⁵ are the same as described above.

The reaction which converts the compound (1ggggg) into the compound (1hhhhh) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) the above described reaction formula 2 in which a hydrogen reducing agent is used.

In the formula, R¹, R², X₁ and Y are the same as described above,

A₂₃ represents a group of the formula:

and A₂₄ represents a group of the formula:

wherein R³ and p are the same as described above.

The reaction which converts the compound (1iiiii) into the compound (1jjjjj) is carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

In the formula, R², X₁ and Y are the same as described above,

A₂₅ represents a group of the formula:

and A₂₆ represents a group of the formula:

wherein B_(4a) represents a lower alkenylene group, B_(4b) represents a lower alkylene group, and R³, p, R¹⁴ and R¹⁵ are the same as described above.

The reaction which converts the compound (1kkkkk) into the compound (1lllll) is carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) in the (1) method of formula 47 described above.

In the formula, R², X₁, Y, and R^(59b) are the same as described above,

A₂₈ represents a group of the formula:

and A₂₇ represents a group of the formula:

wherein R³, p and R^(59b) are the same as described above.

The reaction which converts the compound (1mmmmm) into the compound (1nnnnn) is carried out under reaction conditions similar to those of the hydrolysis B reaction described for the above described reaction formula 9.

The reaction of the compound (1nnnnn) with the compound (100′) is carried out under reaction conditions similar to those of the reaction of the compound (1fff) with the compound (43) of the above described reaction formula 20.

In the formula, R², X₁, X₂ and Y are the same as described above,

A₂₉ represents a group of the formula:

and A₃₀ represents

wherein R⁹⁰ represents a lower alkyl group which may have a hydroxyl group as a substituent, and R³, p and R^(59b) are the same as described above.

The reaction of the compound (1ooooo) with the compound (176) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

In the formula, R², X₁, X₂ and Y are the same as described above,

A₃₁ represents a group of the formula:

and A₃₂ represents

wherein R³, p, R^(59b) and R⁸⁹ are the same as described above.

The reaction of the compound (1qqqqq) with the compound (173) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

In the formula, R¹, R², X₁, Y, A₁₀, T, l, R⁹⁰ and X₂ are the same as described above.

R^(15″) represents the group (2), (3), (4), (5), (6), (7), (8), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (26a), (27a), (28a), (29a), (30a), (31a), (32a), (33a), (34a), (35a), (36a), or (37a), which is defined for the above described R¹⁵ described above.

The reaction of the compound (1sssss) with the compound (176) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

In the formula, R¹, R², X₁, Y, A₁₀, T and l are the same as described above,

R^(14AA) and R^(15BB) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —(B₁₂CO)t-N(R^(20′))—CO—B₁₆X₂ group thereon, R^(14CC) and R^(15DD) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵, except that the heterocyclic ring has at least one —(B₁₂CO)t-N(R^(20′))—CO—B₁₆R⁹¹ group thereon, wherein B₁₂, t, B₁₆ and X₂ are the same as described above, R⁹¹ represents an imidazolyl group, and R^(20′) represents a hydrogen atom, a cycloalkyl group, an amino group which may have a lower alkoxycarbonyl group as a substituent, a benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring, a lower alkyl group, a lower alkyl group which have 1 or 2 phenyls which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent and a lower alkylthio group, a phenyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a lower alkoxy group which may have a halogen atom as a substituent and a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a cycloalkyl lower alkyl group, a pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, an amino substituted lower alkyl group which may have a substituent selected from the group consisting of a phenyl group and a lower alkyl group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a naphthyl lower alkyl group, a pyridyl lower alkyl group, a quinolyl lower alkyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group, a phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group, a phenyl lower alkanoyl group, a lower alkanoyl group which may have a halogen atom as a substituent, an imidazolyl lower alkanoyl group, a lower alkoxycarbonyl lower alkyl group, a pyridyl group or a carboxy lower alkyl group.

The reaction of the compound (1uuuuu) with the compound (177) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

In the formula, X₁, X₂, R², Y, A and R⁶ are the same as described above, and R⁹¹ represents a hydrogen atom or a lower alkyl group.

The reaction of the compound (33) with the compound (178) may also be carried out in an appropriate solvent in the presence of a basic compound and a catalyst. Examples of the inert solvent used include water, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, and hexamethylphosphoric acid triamide, and a mixture thereof.

Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, potassium phosphate, sodium phosphate, sodium hydride, potassium hydride, potassium, sodium, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate, sodium n-butoxide, sodium tert-butoxide, and potassium tert-butoxide, alkylsilylamide alkali metal salts such as potassium bis(trimethylsilyl)amide, and organic bases such as pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), and a mixture thereof.

Examples of the catalyst may include palladium compounds such as palladium acetate, bis(tributyltin)/bis(dibenzylideneacetone)palladium, copper iodide/2,2′-bipyridyl, bis(dibenzylideneacetone)palladium, copper iodide/bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium, R-tris(dibenzylideneacetone)dipalladium, S-tris(dibenzylideneacetone)dipalladium, palladium (II) acetate, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), and tetrakis (triphenylphosphine)palladium, compounds such as R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (R-BINAP), S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), RAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (RAC-BINAP), and 2,2-bis(diphenylimidazolidinyliden), xanthene compounds such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and borates such as tri-tert-butylphosphine tetrafluoroborate, and a mixture thereof.

The basic compound is appropriately used in an amount at least 0.5 times, and preferably 0.5 to 40 times of the compound (33) on a molar basis. The catalyst is appropriately used in a typical catalyst amount based on the compound (33).

The compound (178) is appropriately used in an amount at least in 0.5 times, and preferably 0.5 to 3 times of the compound (33) on a molar basis.

The above described reaction is carried out typically at room temperature to 200° C., preferably at room temperature to about 150° C., and is completed in about 0.5 to 20 hours.

In the formula, B_(o), X₁, R², Y, A₁₇, R⁶ and X₂ are the same as described above, R⁹² represents a R⁶—Z₄— group or R⁶— group and Z₄ represents a lower alkylene group.

The reaction of the compound (64) with the compound (179) may be carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

In the formula R², X₁, Y, A and R⁶ are the same as described above.

The method for converting the compound (30) into the compound (1bbbbbb) is to obtain a compound (1bbbbbb) by subjecting the compound (30) to diazotization and by reacting the diazonium salt thus obtained with the compound (180).

The diazotization reaction 1. may be carried out in an appropriate solvent in the presence of an acid and a diazotizing agent. Examples of the solvent used in the above described reaction include water and acetonitrile. Examples of the acid used include hydrochloric acid, hydrobromic acid, sulfuric acid, tetrafluoroboric acid, and hexafluorophosophoric acid. Examples of the diazotizing agent include metal nitrites such as sodium nitrite and potassium nitrite, lower alkyl nitrites such as t-butyl nitrite and isoamyl nitrite. The acid is appropriately used in an amount typically about 1 to 10 times of the compound (30), and preferably about 1 to 5 times of the compound (30) on a molar basis. The diazotizing agent is appropriately used in an amount typically at least about equimolar to the compound (30), and preferably 1 to 3 times of the compound (30) on a molar basis. The above described reaction is typically carried out at about 0 to 70° C., and preferably at about 0° C. to room temperature, and is completed in about a few minutes to 5 hours. The reaction 2. of the diazonium salt obtained in the reaction 1. with the compound (180) may be carried out in the similar solvent as in the reaction 1 and in the presence of a basic compound. Any of the basic compounds used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used in this reaction. The basic compound is appropriately used in an amount at least equimolar to the compound (30), and preferably 1 to 5 times of the compound (30) on a molar basis. The compound (180) is appropriately used in an amount at least equimolar to the compound (30), and preferably 1 to 5 times of the compound (30) on a molar basis. The above described reaction is carried out typically at about 0 to 70° C., preferably at about 0° C. to room temperature, and is completed in about a few minutes to 5 hours.

In the formula, X₁, R^(8d), Y, A, R² and R⁶ are the same as described above.

The reaction of the compound (30a) with the compound (181) may be carried out in an appropriate solvent in the presence of an acid and a catalyst. Examples of the inert solvent used include water, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, dimethylsulfoxide, N,N-dimethylformamide, and hexamethylphosphoric acid triamide, and a mixture thereof.

Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, sodium hydride, potassium hydride, potassium, sodium, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate, sodium n-butoxide, sodium tert-butoxide, and potassium tert-butoxide, organic bases such as pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), and a mixture thereof.

Examples of the catalyst include palladium compounds such as tetrakis(triphenylphosphine)palladium (0) and dichlorobis(triphenylphosphine)palladium (II), and copper compounds such as copper (II) acetate.

The basic compound is appropriately used in an amount at least equimolar to the compound (30a), and preferably 1 to 5 times of the compound (30a) on a molar basis. The catalyst is appropriately used in an amount 0.001 to 1 times, and preferably 0.01 to 0.5 times of the compound (30a) on a molar basis.

The compound (181) is appropriately used in an amount at least equimolar to the compound (30a), and preferably 1 to 5 times of the compound (30a) on a molar basis.

The above described reaction is carried out typically at −30 to 200° C., and preferably at 0 to 150° C. and is completed in 0.5 to about 30 hours. A molecular sieve such as Molecular Sieves 3A (MS-3A), Molecular Sieves 4A (MS-4A) or the like may be added to the reaction.

In the formula, R⁶, Z₁, X₁, R², Y and A are the same as described above. Z₄ represents a lower alkylene group.

The reaction which converts the compound (1dddddd) into the compound (1eeeeee) may be carried out in an appropriate solvent in the presence of a catalytic hydrogen reducing agent.

Examples of the solvent used include water, fatty acids such as acetic acid, alcohols such as methanol, ethanol, and isopropanol, aliphatic hydrocarbons such as n-hexane, alicyclic hydrocarbons such as cyclohexane, ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, monoglyme, diglyme, and 1,4-dioxane, esters such as methyl acetate, ethyl acetate, and butyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetoamide, and N-methylpyrrolidone, and a mixture thereof.

Examples of the catalytic hydrogen reducing agent include palladium, palladium-black, palladium-carbon, palladium hydroxide-carbon, rhodium-alumina, platinum, platinum oxide, copper chromite, Raney nickel, and palladium acetate.

The above described catalytic hydrogen reducing agent is typically used in an amount 0.01 to 1 times of the compound (1dddddd) on a molar basis.

The above reaction favorably proceeds typically at about −20 to 150° C., and preferably at 0 to 100° C. and, in general, is completed in 0.5 to 20 hours. The hydrogen pressure may be applied typically at 1 to 10 atm.

In the formula, R¹, R², Y, X₁, A₁₀, T and l are the same as described above; R^(14II) and R^(15JJ) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵ except for having at least one phenyl group which has a lower alkoxycarbonyl group on the heterocyclic ring; R^(14EE) and R^(15FF) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵ except for having at least one phenyl group which has a carboxy group on the heterocyclic ring; R^(14GG) and R^(15HH) represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴ and R¹⁵ except for having at least one phenyl group which has a carbamoyl group which may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group on the heterocyclic ring; and R⁹³ and R⁹¹ represent a hydrogen atom, a lower alkyl group or a lower alkoxy lower alkyl group.

The reaction which converts the compound (1hhhhhh) into the compound (1ffffff) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The reaction of the compound (1ffffff) with the compound (182) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

In the formula, X₁, R², Y, A, X₂, k, X₃, R⁶, B_(20a) and d′ are the same as described above.

The reaction of the compound (30) with the compound (183) is carried out under reaction conditions similar to those of the reaction of the compound (30) with the compound (66) of the above described reaction formula 46.

The reaction which converts the compound (184) into the compound (1jjjjjj) may be carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction of the compound (1jjjjjj) with the compound (185) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

When d′ represents 0 in the compound (185), the reaction which converts the compound (1jjjjjj) into the compound (1kkkkkk) may also be carried out in an appropriate solvent in the presence of a halogenated copper such as copper iodide, an alkylglycine such as N,N-dimethylglycine, or an alkali metal phosphate such as potassium phosphate. Any of the solvents used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used here. Halogenated copper or alkylglycine is used in a typical catalyst amount. The alkali metal phosphate is appropriately used in an amount typically equimolar to the compound (1jjjjjj), and preferably 1 to 5 times of the compound (1jjjjjj) on a molar basis. The compound (185) is used in an amount typically 0.5 to 5 times, and preferably 0.5 to 3 times of the compound (1jjjjjj) on a molar basis. The above described reaction is carried out typically at about room temperature to 200° C., preferably at about room temperature to 150° C. and is completed in about 1 to 30 hours.

In the formula, X₂, R², X₁, Y, A and R⁶ are the same as described above.

The reaction of the compound (33) with the compound (186) is carried out under reaction conditions similar to those of the reaction of the compound (33) with the compound (178) of the above described reaction formula 118.

In the formula, X₁, X₂, R², R⁶, Y, A, B_(21a) and c are the same as described above.

The reaction of the compound (33) with the compound (187) is carried out under reaction conditions similar to those of the reaction of the compound (33) with the compound (178) of the above described reaction formula 118.

In the formula, R⁸, R², X₁, Y, A₁₆, X₂, R⁶ and R^(8b) are the same as described above.

The reaction of the compound (188) with the compound (189) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) by the method (d) of the formula 2 in which carboxylic acid halide is reacted with amine.

The reaction of the compound (190) with the compound (191) may be carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

In the formula, R¹, R², X₁, Y and A₁₆ are the same as described above. Xa represents a halogen atom.

The reaction which converts the compound (1oooooo) into the compound (1pppppp) may be carried out in an appropriate solvent in the presence of a catalytic hydrogenation reducing agent and a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate.

Any solvent and catalytic hydrogenation reducing agent, which are used in the reaction which converts the compound (1dddddd) into the compound (1eeeeee) of the above described reaction formula 122, may be used in the above described reaction.

The above described reaction is carried out under hydrogen atmosphere typically at about 1 atm to 20 atm, and preferably at about 1 atm to 10 atm, and at about −30 to 150° C., and preferably at about 0 to 100° C. In general, the reaction is completed in about 1 to 12 hours.

The catalytic hydrogenation reducing agent is typically used at 0.01 to 40 wt %, and preferably 0.01 to 20 wt % of the compound (1oooooo).

The hydrogen donor is typically used in an amount at least equimolar to the compound (1oooooo), and preferably 1 to 10 times of the compound (1oooooo) on a molar basis.

In the formula, A₁₀, X₂, k, X₃, R⁸⁰ and R⁸ are the same as described above; R^(94a) represents a group defined as a substituent (35), (40), (42) or (50), in which o is 1, or (67), (75) to (76), (78), (80) to (81) or (84), in which s is 0, in the case where the above described R¹⁴ and R¹⁵ form a heterocyclic ring; R^(94b) represents a group defined as a substituent (28), (30) to (34), (36) to (39), (41), (43) to (45), (47) or (49), in which t is 1, (50), in which o is 0, (52) to (60), (62) to (66), (70), (77), (79), (82) to (83), (87), (88a) or (90a) in the case where the above described R¹⁴ and R¹⁵ form a heterocyclic ring; and R^(94c) represents a group defined as a substituent (28), (30) to (34), (39), (41), (45), (47) or (49), in which t is 1, and (50), in which o is 0, (54) to (58), (62) to (64), (66), (70), (79) or (82) to (83) in the case where the above described R¹⁴ and R¹⁵ form a heterocyclic ring, a phenyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkanoyl group, an amino group which may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxy group and a lower alkylenedioxy group, a pyridyl group which may have, on the pyridine ring, 1 to 3 substituents selected from the group consisting of a hydroxy group and a lower alkyl group which may have a hydroxyl group as a substituent, a pyrrolyl group which may have 1 to 3 lower alkyl groups as substituents, a benzoxazolyl group, a benzothiazolyl group, a furyl group, a lower alkyl group which may have a substituent selected from the group consisting of a hydroxy group and a halogen atom, a naphthyl group, a 1,2,3,4-tetrahydronaphthyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a quinolyl group, a 1,2,3,4-tetrazolyl group which may have, on the tetrazole ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group; a thiazolyl group which may have a phenyl group as a substituent on the thiazole ring; a benzoyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom, a pipe idinyl group which may have a lower alkyl group as substituent on the piperidine ring, a 1,2,3,4-tetrahydroquinolyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring, a 1,3,4-oxadiazolyl group which may have an oxo group as a substituent on the 1,3,4 oxadiazole ring, a cycloalkyl group, a thienyl group, or an imidazolyl group.

The reaction of the compound (192) with the compound (183) may be carried out under reaction conditions similar to those of the reaction of the compound (30) with the compound (183) of the above described reaction formula 124.

The reaction which converts the compound (193) into the compound (1qqqqqq) may be carried out under reaction conditions similar to those of the reaction which converts the compound (184) into the compound (1jjjjjj) of the above described reaction formula 124.

The reaction of the compound (1qqqqqq) with the compound (195) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

When R^(94b) of the compound (195) represents (36) to (38), (43), (44), (53), (59) to (60), (87), (88a) or (90a), the reaction of the compound (1qqqqqq) with the compound (195) may also be carried out in an appropriate solvent in the presence of a copper halide such as copper iodide, an alkylglycine such as N,N-dimethylglycine, or an alkali metal phosphate such as potassium phosphate. In the above described reaction, any of the solvents used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used. The copper halide and alkylglycine are used in a normal catalyst amount. The alkali metal phosphate is appropriately used in an amount typically at least in equimolar to the compound (1qqqqqq), and preferably 1 to 5 times of the compound (1qqqqqq) on a molar basis. The compound (195) is appropriately used in an amount typically 0.5 to 5 times, and preferably 0.5 to 3 times of the compound (1qqqqqq) on a molar basis. The above described reaction is carried out typically at room temperature to 200° C., and preferably about room temperature to 150° C., and is completed in about 1 to 30 hours.

The reaction of the compound (1qqqqqq) with the compound (194) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (1qqqqqq) with the compound (196) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described formula 2.

In the formula, X₁, Y, A, R², R⁶, B_(22a), e and X₂ are the same as described above, and R^(10a′) represents a lower alkyl group.

The reaction of the compound (1uuuuuu) with the compound (197) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described formula 2.

In the formula, X₁, Y, A, R², R⁶ and X₂ are the same as described above. R^(10b′) represents a lower alkyl group.

The reaction of the compound (1wwwwww) with the compound (197a) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

In the formula, R¹, X₁, R², Y, A₁₀, X₂, R^(14a) and R^(59b) the same as described above, and R⁹⁶ represents a piperazinyl group which may have, on the piperazine ring, 1 to 3 substituents selected from the group consisting of a phenyl lower alkyl group (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group) and a pyridyl lower alkyl group.

The reaction of the compound (198) with the compound (199) may be carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction which converts the Compound (200) into the compound (201) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The reaction of the compound (201) with the compound (100′) is carried out under reaction conditions similar to those of the reaction of the compound (120b) with the compound (100′) of the above described reaction formula 79.

The reaction of the compound (201) with the compound (202) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The compound (200) may also be produced by the method of the following reaction formula 133:

wherein R^(74a), R², X₁, Y, A₁₃, R^(59b) and X₂ are the same as described above, and R^(14a′) represents a lower alkyl group which may have a hydroxy group as a substituent.

The reaction of the compound (200a) with the compound (203) may be carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (3) may also be produced by the method of the following reaction formula 134:

wherein R⁸⁰, A₁₀, B_(23a), R¹⁴ and R¹⁵ are the same as described above.

The reaction which converts the compound (108l) into the compound (108m) may be carried out under reaction conditions similar to those of the reaction which converts the compound (1f) into the compound (1g) of the above described reaction formula 3.

In the formula, R¹, R², X₁, Y, A₁₀, B_(23a), R⁴ and R¹⁵ are the same as described above.

The reaction which converts the compound (1zzzzzz) into the compound (1AAAAAA) may be carried out under reaction conditions similar to those of the reaction which converts the compound (64b) into the compound (26a) of the above described reaction formula 89 described above.

Each of the target compounds obtained by the formulas shown above may be isolated and purified by separating the crude reaction product from the reaction mixture after cooling using an isolation procedure such as filtration, concentration, or extraction, and by purifying using a common purification procedure such as column chromatography or re-crystallization.

The compound of the present invention represented by the general formula (1) includes a stereoisomers and an optical isomer.

The compound of the present invention, which has a basic group, may easily form a salt with a common pharmacologically acceptable acid. Examples of such an acid include mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malonic acid, and lactic acid.

The compound of the present invention, which has an acidic group, may easily form a salt with a common pharmacologically acceptable basic compound. Examples of such a basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.

Next, medical formulations which contain the compound of the present invention as an active ingredient will be described.

The above described medical formulations, which are obtained by preparing the compound of the present invention formulated into a common pharmaceutical form, are prepared using a diluent or excipient commonly used such as a filler, expander, binder, moistener, disintegrator, surfactant, or lubricant.

Such medical formulations may be chosen from various forms according to the therapeutic objectives, and typical examples of such formulations include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions).

Carriers which are used for forming tablets may be chosen widely from the conventional ones, of which examples include excipients such as lactose, saccharose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose, binders such as water, ethanol, propanol, simple syrup, a glucose solution, a starch solution, a gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone, disintegrators such as dried starch, sodium arginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose, anti-disintegrators such as saccharose, stearine, cacao butter, and hydrogenated oil, absorbefacients such as quartenary ammonium base, and sodium lauryl sulfate, wetting agents such as glycerol and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicate, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol.

Further, tablets may be made into conventional coated tablets, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double or multi-layered tablets.

Carriers which are used for forming pills may be chosen widely from the conventional ones, of which examples include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrators such as laminaran and agar.

Carriers which are used for forming suppositories may be chosen widely from the conventional ones, of which examples include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

The injection preparations in liquid, emulsion and suspension forms are preferably sterilized and isotonic with the blood. Diluents which are used for forming these liquid, emulsion and suspension preparations may be chosen widely from the conventional ones, of which examples include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid ester. In this case, the medical formulations may contain sodium chloride, glucose or glycerol enough to prepare isotonic solutions. Also, conventional solubilizers, buffers, analgestics, and the like, and, as necessary, coloring agents, preservatives, spices, flavors, sweets and the like, or other pharmaceuticals may be added.

Although the amount of the compound of the present invention included in the medical formulation is not limited and may be selected appropriately in a wide range, it is typically preferable that the medical formulation contains the compound of the present invention at 1 to 70 wt %.

The method for administration of the medical formulation of the present invention is not limited and the administration is carried out in accordance with the conditions such as forms of the medical formulation, patient's age, sex, severity of the disease and other conditions. For example, tablets, pills, liquids, suspensions, emulsions, granules and capsules are administered orally. The injection formulations are administered intravenously singly or by mixing with a conventional fluid replacement such as a glucose solution or amino acid solution, or, as necessary, administered singly and intramuscularly, intradermally, subcutaneously or intraperitoneally. The suppositories are administered into the rectum.

The dosage for the above mentioned medical formulation may be chosen appropriately according to the usage, patient's age, sex and severity of the disease and other conditions. Typically, 0.001 to 100 mg per kg body weight per day, preferably 0.001 to 50 mg per kg body weight per day, is administered once or in several times a day.

Since the above described dosage may vary in accordance with various conditions, it may be sufficient with a dosage smaller than in the above described range, or it may be necessary to administer a dosage larger than in the above described range.

The compound of the present invention has a superior effect on suppressing the production of collagen.

The compound of the present invention has lower side effects and is excellent in safety.

EXAMPLES

The present invention is explained in more detail by illustrating Reference Examples, Examples, Formulation Example and Pharmacological Test as follows.

Reference Example 1 Production of 1-(t-butoxycarbonyl)-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine Step 1 Production of 1-(t-butoxycarbonyl)-4-[(4-methoxymethoxy)phenyl]-4-hydroxypiperidine

A solution of 1-bromo-4-methoxymethoxybenzene (5.43 g, 25.0 mmol) in tetrahydrofuran (THF) (100 mL) Was stirred at −85° C., and a 2.46 M n-butyllithium hexane solution (10.2 mL, 25.0 mmol) was added dropwise to the stirred solution over 10 minutes. The resulting solution was stirred at the same temperature for 40 minutes. To the reaction solution was added dropwise for 10 minutes a solution of 1-(t-butoxycarbonyl)-4-piperidone (5.20 g, 26.0 mmol) in THF (30 mL). The temperature of the resulting solution was raised to −25° C. over 4 hours, and then the solution was stirred at that temperature for 2 hours. An aqueous solution of saturated ammonium chloride was then added to this solution. The reaction solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, after which the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3, in ratio by volume; hereinafter the same), to thereby yield 7.63 g of the title compound.

Appearance: Colorless oil

¹H NMR (CDCl₃) δ 1.49 (9H, s), 1.73 (2H, d, J=12.0 Hz), 1.97 (2H, brs), 3.24 (2H, brs), 3.48 (3H, s), 4.00 (2H, brs), 5.17 (2H, s), 7.03 (2H, d, J=9.0 Hz), 7.39 (2H, d, J=9.0 Hz).

Step 2 Production of 1-(t-butoxycarbonyl)-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine

To a solution of 1-(t-butoxycarbonyl)-4-[(4-methoxymethoxy)phenyl]-4-hydroxypiperidine (5.32 g, 15.8 mmol) in toluene (100 mL) was added p-toluenesulfonic acid monohydrate (0.56 g, 2.95 mmol), and the resulting solution was refluxed for 21 hours. The reaction solution was cooled to room temperature, and evaporated under reduced pressure. To this crude product were added ethanol (60 mL) and 2 M hydrochloric acid (40 mL, 80 mmol), and the resulting solution was stirred for 2 hours at 60° C. The reaction solution was again cooled to room temperature, and evaporated under reduced pressure. To the residue were added methanol (100 mL), triethylamine (9.0 mL, 64.6 mmol) and di-t-butyl dicarbonate (5.20 g, 23.8 mmol), and the resulting solution was stirred for 24 hours at room temperature. The solvent was evaporated under reduced pressure, after which to the residue was added 100 mL of ethyl acetate. Insoluble matter was removed by filtration, after which the filtrate was evaporated under reduced pressure. To the residue were added 1,4-dioxane (50 mL) and a 1 M aqueous solution of sodium hydroxide (50 mL, 50 mmol) and stirred for 14 hours at 60° C. To the resulting reaction solution was added at room temperature 2 M hydrochloric acid (25 mL, 50 mmol) to neutralize, and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated to thereby yield 4.10 g of the title compound.

Appearance: Brown amorphous

¹H NMR (CDCl₃) δ 1.49 (9H, s), 2.47 (2H, brs), 3.62 (2H, t, J=5.5 Hz), 4.05 (2H, brs), 5.91 (1H, brs), 6.81 (2H, d, J=9.0 Hz), 7.25 (2H, d, J=9.0 Hz).

Reference Example 2 Production of methyl 5-(4-benzylpiperazin-1-yl)-2-methoxymethoxybenzoate

To a solution of methyl 5-chloro-2-methoxymethoxybenzoate (1.45 g, 6.29 mmol) and 1-benzylpiperazine (1.66 g, 9.43 mmol) in toluene (50 mL) were added palladium acetate (28 mg, 0.126 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (157 mg, 0.252 mmol) and cesium carbonate (3.07 g, 9.43 mmol), and the resulting solution was refluxed for 3 hours. Water was added to the resulting solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to thereby yield 400 mg of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 2.59-2.62 (4H, m), 3.12-3.16 (4H, m), 3.51 (3H, s), 3.57 (2H, s), 3.88 (3H, s), 5.16 (2H, s), 7.01 (1H, dd, J=9.1 Hz, 3.1 Hz), 7.10 (1H, d, J=9.1 Hz), 7.28-7.35 (6H, m).

The following compounds were produced in the same manner as in Reference Example 2.

TABLE 1

Reference Example No. R₁₀₁ R₁₀₂ R₁₀₃ ¹H NMR (CDCl₃) δ ppm 3 —CH₂OCH₃

—H 1.27 (3H, t, J = 7.0 Hz), 1.43- 1.48 (2H, m), 1.83 (2H, brd, J = 13.0 Hz), 1.90 (1H, m), 2.28 (2H, d, J = 7.0 Hz), 2.66 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.47 (3H, s), 3.50 (2H, brd, J = 12.0 Hz), 4.15 (2H, q, J = 7.0 Hz), 5.10 (2H, s), 6.89 (2H, d, J = 9.0 Hz), 6.95 (2H, d, J = 9.0 Hz). 4 —CH₂OCH₃

—H 1.27 (3H, t, J = 7.0 Hz), 1.57- 1.75 (2H, m), 1.82 (1H, m), 2.00 (1H, m), 2.68-2.75 (2H, m), 2.93 (1H, dd, J = 10.0 Hz, 12.0 Hz), 3.34 (1H, d, J = 12.0 Hz), 3.48 (3H, s), 3.56 (1H, brd, J = 10.0 Hz), 4.16 (2H, q, J = 7.0 Hz), 5.11 (2H, s), 6.91 (2H, d, J = 9.0 Hz), 6.96 (2H, d, J = 9.0 Hz). 5 —CH₃

—H 1.27 (3H, t, J = 7.0 Hz), 1.9 (2H, dq, J = 3.0 Hz, 13.5 Hz), 2.02 (2H, dd, J = 13.5 Hz, 3.0 Hz), 2.38 (1H, m), 2.69 (2H, dt, J = 3.0 Hz, 12.0 Hz), 3.48 (2H, dt, J = 12.0 Hz, 3.0 Hz), 3.37 (3H, s), 4.16 (2H, q, J = 7.0 Hz), 6.83 (2H, d, J = 9.0 Hz), 6.91 (2H, d, J = 9.0 Hz). 6 —CH₂OCH₃

—CH₃ 1.27 (3H, t, J = 7.1 Hz), 1.82- 1.99 (4H, m), 2.22 (3H, s), 2.33- 2.42 (1H, m), 2.64-2.73 (2H, m), 3.50-3.52 (5H, m), 4.15 (2H, q, J = 7.1 Hz), 5.12 (2H, s), 6.70 (1H, dd, J = 8.9 Hz, 3.1 Hz), 6.78 (1H, d, J = 3.0 Hz), 6.95 (1H, d, J = 8.7 Hz). 7 —CH₂OCH₃

—OCH₃ 1.27 (3H, t, J = 7.1 Hz), 1.37- 1.47 (2H, m), 1.81-1.94 (3H, m), 2.29 (2H, d, J = 6.9 Hz), 2.64- 2.73 (2H, m), 3.51 (3H, s), 3.54 (2H, brs), 3.85 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 5.13 (2H, s), 6.44 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.56 (1H, d, J = 2.6 Hz), 7.02 (1H, d, J = 8.7 Hz). 8 —CH₂OCH₃

—CH₃ 1.27 (3H, t, J = 7.1 Hz), 1.37- 1.49 (2H, m), 1.80-2.04 (3H, m), 2.22 (3H, s), 2.27 (2H, d, J = 6.9 Hz), 2.60-2.68 (2H, m), 3.48 (3H, s), 3.52 (2H, brs), 4.14 (2H, q, J = 7.1 Hz), 5.11 (2H, s), 6.69-6.79 (2H, m), 6.94 (1H, d, J = 8.7 Hz).

TABLE 2

Reference Example No. R₁₀₄ ¹H NMR (CDCl₃) δ ppm 9

1.48 (9H, s), 1.76-1.89 (4H, m), 2.78 (3H, brs), 2.81 (2H, brt, J = 12.0 Hz), 3.71 (2H, brd, J = 12.0 Hz), 4.15 (1H, brs), 6.96 (2H, d, J = 9.0 Hz), 6.98 (4H, s), 8.17 (2H, d, J = 9.0 Hz). 10

1.49 (9H, s), 3.13 (4H, t, J = 5.0 Hz), 3.60 (4H, t, J = 5.0 Hz), 6.96-7.00 (6H, m), 8.18 (2H, d, J = 9.0 Hz). 11

1.79 (2H, m), 2.03 (2H, m), 2.96 (2H, m), 3.41 (3H, s), 3.51 (2H, m), 3.73 (1H, m), 4.74 (2H, s), 6.95-6.98 (6H, m), 8.17 (2H, d, J = 9.0 Hz). 12

1.28 (3H, t, J = 7.0 Hz), 1.90 (2H, dq, J = 4.0 Hz, 13.0 Hz), 2.05 (2H, dd, J = 13.0 Hz, 4.0 Hz), 2.45 (1H, m), 2.82 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.62 (2H, brd, J = 12.5 Hz), 4.17 (2H, q, J = 7.0 Hz), 6.95-6.98 (6H, m), 8.17 (2H, d, J = 9.0 Hz). 13

1.31 (3H, t, J = 7.0 Hz), 1.83 (2H, m), 2.05 (2H, m), 2.96 (1H, m), 3.07 (1H, m), 3.46 (1H, m), 3.53 (1H, m), 3.60 (1H, m), 4.16 (2H, s), 4.24 (2H, q, J = 7.0 Hz), 6.95-7.01 (6H, m), 8.17 (2H, d, J = 9.0 Hz).

Reference Example 14 Production of methyl 5-(4-benzylpiperazin-1-yl)-2-hydroxybenzoate

To a solution of 400 mg of methyl 5-(4-benzylpiperazin-1-yl)-2-methoxymethoxybenzoate (1.1 mmol) in 1,4-dioxane (20 mL) was added a solution of 4 N hydrogen chloride in 1,4-dioxane (4 mL, 16 mmol), and the resulting solution was stirred for 2 hours at 100° C. The resulting reaction solution was subjected to distillation under reduced pressure to obtain a residue. This residue was purified by silica gel column chromatography (dichloromethane:methanol 30:1), to thereby yield 353 mg of the title compound.

Appearance: Pale yellow powder

¹H NMR (CD₃OD) δ 3.29-3.40 (8H, m), 3.94 (3H, s), 4.39 (2H, s), 6.91 (1H, d, J=8.9 Hz), 7.28 (1H, dd, J=8.9 Hz, 3.0 Hz), 7.42 (1H, d, J=3.0 Hz), 7.49-7.60 (5H, m).

The following compounds were produced in the same manner as in Reference Example 14.

TABLE 3

Reference Example No. R₁₀₅ R₁₀₆ Form ¹H NMR (solvent) δ ppm 15 —H

free (DMSO-d₆) 1.20 (3H, t, J = 7.0 Hz), 1.78 (2H, brs), 1.91 (2H, brs), 2.10 (1H, brs), 2.34 (2H, brs), 3.45 (2H, brs), 3.55 (2H, brs), 4.09 (2H, q, J = 7.0 Hz), 6.88 (2H, brs), 7.60 (2H, brs), 10.05 (1H, brs), 11.75 (1H, brs). 16 —H

free (DMSO-d₆) 1.20 (3H, t, J = 7.0 Hz), 1.64 (1H, brs), 1.93 (2H, brs), 2.08 (2H, brs), 3.30 (1H brs), 3.45 (2H, brs), 3.48 (2H, brs), 4.10 (2H, q, J = 7.0 Hz), 6.88 (2H, brs), 7.66 (2H, brs), 10.05 (1H, brs), 12.60 (1H, brs). 17 —CH₃

hydro- chloride (DMSO-d₆) 1.22 (3H, t, J = 7.1 Hz), 2.03-2.13 (4H, m), 2.14 (3H, s), 2.75 (1H, brs), 3.38-3.57 (4H, m), 4.12 (2H, q, J = 7.1 Hz), 6.89 (1H, d, J = 8.6 Hz), 7.46-7.53 (2H, m), 9.99 (1H, brs). 18 —OCH₃

free (CDCl₃) 1.27 (3H, t, J = 7.1 Hz), 1.98-2.18 (3H, m), 2.41-2.44 (4H, m), 3.30 (2H, t, J = 12.0 Hz), 3.66 (2H, d, J = 11.9 Hz), 3.95 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 6.26 (1H, brs), 6.96-7.03 (2H, m), 7.85 (1H, s). 19 —CH₃

hydro- chloride (DMSO-d₆) 1.20 (3H, t, J = 7.1 Hz), 1.87 (4H, brs), 2.14 (4H, brs), 2.33 (2H, d, J = 6.4 Hz), 2.52 (2H, brs), 3.44 (2H, brs), 4.19 (2H, q, J = 7.1 Hz), 6.88 (1H, d, J = 8.6 Hz), 7.46-7.57 (2H, m), 9. 98 (1H, brs), 12.04 (1H, brs).

Reference Example 20 Production of ethyl N-(4-hydroxyphenyl)isonipecotate

To a solution of ethyl N-(4-methoxyphenyl)isonipecotate (2.63 g, 10 mmol) in dichloromethane (100 mL) was added a solution of 2 M boron tribromide in dichloromethane (20 mL, 40 mmol), and the resulting solution was stirred for 0.5 hours at room temperature. The resulting reaction solution was poured into ice water, then an aqueous solution of 1 M sodium hydroxide (110 mL) was added to the solution. After stirring, the resulting solution was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to thereby yield 2.43 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.0 Hz), 1.91 (2H, m), 2.02 (2H, brd, J=11.5 Hz), 2.38 (1H, m), 2.68 (2H, dt, J=2.0 Hz, 11.5 Hz), 3.46 (2H, dt, J=12.0 Hz, 3.0 Hz), 4.16 (2H, q, J=7.0 Hz), 4.45 (1H, brs), 6.75 (2H, d, J=9.0 Hz), 6.86 (2H, d, J=9.0 Hz).

The following compounds were produced in the same manner as in Reference Example 20.

Reference Example 21 4-(2-Fluoro-4-nitrophenoxy)phenol

¹H NMR (DMSO-d₆) δ 6.80-7.10 (5H, m), 8.04 (111, ddd, J=1.4 Hz, 2.7 Hz, 9.2 Hz), 8.29 (1H, dd, J=2.7 Hz, 10.9 Hz), 9.59 (1H, s).

Reference Example 22 1-Benzyl-3-(4-hydroxyphenyl)imidazolidin-2-one

¹H NMR (DMSO-d₆) δ 3.18-3.40 (2H, m), 3.61-3.80 (2H, m), 4.35 (2H, s), 6.71 (2H, d, J=8.8 Hz), 7.15-7.48 (7H, m), 9.10 (1H, s).

Reference Example 23 Production of 2-(4-hydroxyphenylamino)-1-(4-piperonylpiperazin-1-yl)ethanone

To a solution of N-(4-hydroxyphenyl)glycine (11.38 g, 68.1 mmol) in N,N-dimethylformamide (DMF) (150 mL) were added under ice cooling 1-piperonylpiperazine (15.0 g, 68.1 mmol), 1-hydroxybenzotriazole monohydrate (10.43 g, 68.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.66 g, 81.7 mmol), and the resulting solution was stirred for 30 minutes under ice cooling and for 4.5 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution (400 mL), and extracted with ethyl acetate (400 mL). The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to leave the resulting product solidified in a powdered form. Ethyl acetate was added, and the resulting product was filtered off and washed with ethyl acetate, to thereby yield 18.58 g of the title compound.

Appearance: Brown powder

¹H NMR (DMSO-d₆) δ 2.30 (2H, brs), 2.36 (2H, brs), 3.40 (2H, s), 3.47 (4H, t, J=14.5 Hz), 4.03 (2H, d, J=7.0 Hz), 4.90 (1H, brs), 5.99 (2H, s), 6.49 (2H, d, J=8.9 Hz), 6.54 (2H, d, J=8.9 Hz), 6.75 (1H, dd, J=8.0 Hz, 1.1 Hz), 6.85 (1H, d, J=8.0 Hz), 6.87 (1H, s), 8.42 (1H, s).

The following compounds were produced in the same manner as in Reference Example 23.

Reference Example 24 6-Chloro-N-(3,4-dichlorophenyl)nicotinamide

¹H NMR (CDCl₃) δ 7.64 (1H, d, J=8.9 Hz), 7.72 (1H, dd, J=8.7 Hz, 2.3 Hz), 7.73 (1H, dd, J=8.3 Hz, 0.7 Hz), 8.12 (1H, d, J=2.3 Hz), 8.35 (1H, dd, J=8.3 Hz, 2.5 Hz), 8.95 (1H, dd, J=2.5 Hz, 0.7 Hz), 10.71 (1H, brs).

Reference Example 25 4-(4-Piperonylpiperazine-1-carbonyl)-1-(4-hydroxyphenyl)pyrrolidin-2-one

¹H NMR (CDCl₃) δ 2.43-2.43 (4H, m), 2.73-2.95 (2H, m), 3.45 (2H, s), 3.49-3.54 (4H, m), 3.65-3.72 (1H, m), 3.78-3.87 (1H, m), 4.17-4.23 (1H, m), 5.96 (2H, s), 6.71-6.80 (4H, m), 6.84-6.85 (1H, m), 7.29 (2H, d, J=8.9 Hz).

TABLE 4

Reference Example No. X_(a1) X_(a2) R₁₀₇ R₁₀₈ Form ¹H NMR (solvent) δ ppm 26 —NH— —CH₂— —H benzyl free (CDCl₃) 2.46-2.48 (4H, m), 3.45 (2H, t, J = 5.0 Hz), 3.54 (2H, s), 3 68 (2H, t, J = 5.0 Hz), 3.82 (2H, s), 6.53 (2H, d, J = 8.7 Hz), 6.70 (2H, d, J = 8.7 Hz), 7.27- 7.34 (5H, m). 27 —CH₂— —CH₂— —H benzyl free (CDCl₃) 2.30-2.33 (2H, m), 2.41- 2.45 (2H, m), 2.55-2.60 (2H, m), 2.85- 2.91 (2H, m), 3.36-3.40 (2H, m), 3.52 (2H, s), 3.62-3.66 (2H, m), 5.10 (1H, brs), 6.74-6.77 (2H, m), 7.03 (2H, d, J = 8.6 Hz), 7.27-7.32 (5H, m). 28 —CH₂— —CH₂— —H piperonyl hydro- (DMSO-d₆) 2.56-3.47 (10H, m), 4.01- chloride 4.07 (1H, m), 4.18-1.48 (3H, m), 6.07 (2H, s), 6.65-6.68 (2H, m), 7.00-7.03 (4H, m), 7.21 (1H, s), 9.18 (1H, brs), 11.04 (1H, brs). 29 —O— —CH₂— —H piperonyl free (CDCl₃) 2.31-2.50 (4H, m), 3.41 (2H, s), 3.52-3.72 (4H, m), 4.63 (2H, s), 5.94 (2H, s), 6.25 (1H, brs), 6.70 (2H, d, J = 9.1 Hz), 6.69-6.77 (1H, m), 6.73 (1H, s), 6.77 (2H, d, J = 9.1 Hz), 6.83 (1H, d, J = 0.9 Hz). 30 —O— —CH₂— —H benzyl free (CDCl₃) 2.40-2.52 (4H, m), 3.51 (2H, s), 3.53-3.73 (4H, m), 4.63 (2H, s), 5.89 (1H, brs), 6.70 (2H, d, J = 9.2 Hz), 6.78 (2H, d, J = 9.2 Hz), 7.22-7.43 (5H, m). 31 —CH(OH)— none —H benzyl free (CDCl₃) 1.89-2.03 (1H, m), 2.21- 2.32 (1H, m), 2.32-2.57 (2H, m), 3.00- 3.18 (1H, m), 3.20-3.35 (1H, m), 3.40 (1H, d, J = 13.1 Hz), 3.46 (1H, d, J = 13.1 Hz), 3.60-3.83 (2H, m), 5.13 (1H, s), 6.71 (2H, d, J = 8.6 Hz), 7.09 (2H, d, J = 8.6 Hz), 7.18-7.35 (5H, m). 32 none none —H 3-pyridyl free (DMSO-d₆) 3.18-3.35 (4H, m), 3.64 (4H, brs), 6.82 (2H, d, J = 8.4 Hz), 7.21- 7.37 (4H, m), 8.02-8.03 (1H, m), 8.32 (1H, d, J = 2.4 Hz), 9.90 (1H, brs). 33 —CH₂— —CO— —H —CO₂C(CH₃)₃ free (CDCl₃) 1.44 (9H, s), 2.93-3.15 (4H, m), 3.32 (2H, t, J = 5.2 Hz), 3.50 (2H, t, J = 5.2 Hz), 3.97 (2H, s), 5.48 (1H, brs), 6.81 (2H, d, J = 8.6 Hz), 7.11 (2H, d, J = 8.6 Hz). 34 —NH— —CH₂— —CH₃ piperonyl free (CDCl₃) 2.20 (3H, s), 2.41-2.46 (4H, m), 3.44 (4H, brs), 3.67 (2H, t, J = 4.8 Hz), 3.81 (2H, s), 4.34 (1H, brs), 4.52 (1H, brs), 5.95 (2H, s), 6.37 (1H, dd, J = 8.4 Hz, 2.6 Hz), 6.44 (1H, d, J = 2.8 Hz), 6.64 (1H, d, J = 8.4 Hz), 6.70-6.77 (2H, m), 6.85 (1H, s).

Reference Example 35

Production of ethyl (4-hydroxy-3-methylphenylamino)acetate

Potassium carbonate (5.04 g, 36.5 mmol) was added at room temperature to a solution of 4-amino-o-cresol (3.00 g, 24.4 mmol) and ethyl bromoacetate (2.70 mL, 24.4 mmol) in DMF (30 mL). The resulting solution was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 5.10 g of the title compound.

Appearance: Yellow solid

¹H NMR (CDCl₃) δ 1.28 (3H, t, J=7.1 Hz), 2.19 (3H, s), 3.84 (2H, s), 3.95 (1H, brs), 4.22 (2H, q, J=7.1 Hz), 4.59 (1H, brs), 6.36 (1H, dd, J=8.4 Hz, 2.9 Hz), 6.44 (1H, d, J=2.9 Hz), 6.63 (1H, d, J=8.4 Hz).

The following compounds were produced in the same manner as in Reference Example 35.

Reference Example 36 Ethyl (3-hydroxyphenylamino)acetate

¹H NMR (CDCl₃) δ 1.30 (3H, t, J=7.1 Hz), 3.88 (2H, s), 4.25 (2H, q, J=7.1 Hz), 4.29 (1H, brs), 4.85 (1H, s), 6.08-6.10 (1H, m), 6.18-6.24 (2H, m), 7.01-7.07 (1H, m).

Reference Example 37 Benzyl (4-hydroxy-3-methoxyphenylamino)acetate

¹H NMR (CDCl₃) δ 3.81 (3H, s), 3.92 (2H, brs), 4.01 (1H, brs), 5.09 (1H, brs), 5.20 (2H, s), 6.11 (1H, dd, J=8.4 Hz, 2.6 Hz), 6.23 (1H, d, J=2.6 Hz), 6.76 (1H, d, J=8.4 Hz), 7.31-7.38 (5H, m).

Reference Example 38 t-Butyl [3-(4-benzyloxy-3-methylphenyl)-2-oxotetrahydropyrimidin-1-yl]acetate

¹H NMR (CDCl₃) δ 1.47 (9H, s), 2.04-2.21 (2H, m), 2.25 (3H, s), 3.45 (2H, t, J=5.9 Hz), 3.67 (2H, t, J=5.9 Hz), 4.04 (2H, s), 5.06 (2H, s), 6.82 (1H, d, J=8.6 Hz), 7.01 (1H, dd, J=2.6 Hz, 8.6 Hz), 7.06-7.12 (1H, m), 7.26-7.48 (5H, m).

TABLE 5

Reference Example No. R₁₀₉ R₁₁₀ R₁₁₁ R₁₁₂ R₁₁₃ ¹H NMR (CDCl₃) δ ppm or MS 39 —CH₃ —CH₃ —H —H —H ¹H NMR 1.30 (3H, t, J = 7.1 Hz), 2.14 (3H, s), 2.20 (3H, s), 3.87 (2H, s), 4.24 (2H, q, J = 7.1 Hz), 4.42 (1H, brs), 6.29 (1H, d, J = 8.6 Hz), 6.58 (1H, d, J = 8.6 Hz). 40 —F —H —F —H —H ¹H NMR 1.30 (3H, t, J = 7.1 Hz), 3.85 (2H, s), 4.25 (2H, q, J = 7.1 Hz), 4.77 (1H, s), 6.37 (1H, dd, J = 7.9 Hz, 11.8 Hz), 6.73 (1H, dd, J = 7.9 Hz, 11.6 Hz). 41 —CH₃ —H —CH₃ —H —H ¹H NMR 1.30 (3H, t, J = 7.1 Hz), 2.15 (3H, s), 2.19 (3H, s), 3.84 (1H, brs), 3.89 (2H, s), 4.17 (1H, s), 4.25 (2H, q, J = 7.1 Hz), 6.28 (1H, s), 6.57 (1H, s). 42 —H —CH₃ —CH₃ —H —H MS 223 (M⁺) 43 —OCH₃ —H —H —H —H ¹H NMR 1.29 (3H, t, J = 7.1 Hz), 3.82 (3H, s), 3.85 (2H, s), 4.23 (2H, q, J = 7.1 Hz), 5.26 (1H, brs), 6.11 (1H, dd, J = 8.4 Hz, 2.6 Hz), 6.25 (1H, d, J = 2.6 Hz), 6.76 (1H, d, J = 8.4 Hz). 44 —F —H —H —H —H ¹H NMR 1.30 (3H, t, J = 7.1 Hz), 3.83 (2H, s), 4.08(1H, brs), 4.24 (2H, q, J = 7.1 Hz), 4.62 (1H, d, J = 3.3 Hz), 6.30-6.41 (2H, m), 6.85 (1H, t, J = 8.9 Hz). 45 —H —H —H —CH₃ —CH₃ ¹H NMR 1.20 (3H, t, J = 7.1 Hz), 1.48 (6H, s), 4.15 (2H, q, J = 7.1 Hz), 6.60-6.69 (4H, m). 46 —CH₃ —H —H —CH₃ —H ¹H NMR 1.24 (3H, t, J = 7.3 Hz), 1.44 (3H, d, J = 6.9 Hz), 2.18 (3H, s), 3.80 (1H, brs), 4.03 (1H, q, J = 6.9 Hz), 4.17 (2H, q, J = 7.3 Hz), 4.25 (1H, brs), 6.37 (1H, dd, J = 8.4 Hz, 3.0 Hz), 6.45 (1H, d, J = 2.8 Hz), 6.62 (1H, d, J = 8.4 Hz). 47 —H —H —H —CH₃ —H ¹H NMR 1.24 (3H, t, J = 7.1 Hz), 1.44 (3H, d, J = 6.7 Hz), 3.88 (1H, brs), 4.04 (1H, q, J = 6.9 Hz), 4.17 (2H, q, J = 7.1 Hz), 4.59 (1H, brs), 6.54 (2H, d, J = 8.9 Hz), 6.68 (2H, d, J = 8.9 Hz). 48 —CF₃ —H —H —H —H MS 263 (M⁺)

TABLE 6

Reference Example No. R₁₁₄ R₁₁₅ R₁₁₆ R₁₁₇ R₁₁₈ ¹H NMR (solvent) δ ppm or MS 49

—H —H —H —H ¹H NMR (DMSO-d₆) 1.18 (3H, t, J = 7.1 Hz), 3.89 (2H, d, J = 6.2 Hz), 4.11 (2H, q, J = 7.1 Hz), 6.14 (1H, t, J = 6.2 Hz), 6.62 (2H, d, J = 8.8 Hz), 6.90 (1H, t, J = 9.0 Hz), 6.97 (2H, d, J = 8.8 Hz), 8.03 (1H, dd, J = 2.6 Hz, 9.0 Hz), 8.24 (1H, dd, J = 2.6 Hz. 10.9 Hz). 50

—F —H —F —CH₃ ¹H NMR (CDCl₃) 1.29 (3H, t, J = 7.1 Hz), 3.07 (3H, s), 4.03 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.22- 6.35 (2H, m), 7.15 (1H, d, J = 9.0 Hz), 8.49 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.01 (1H, d, J = 2.8 Hz). 51

—F —F —H —CH₃ ¹H NMR (CDCl₃) 1.28 (3H, t, J = 7.1 Hz), 3.05 (3H, s), 4.06 (2H, s), 4.20 (2H, q, J = 7.1 Hz), 6.72 (1H, td, J = 2.2 Hz, 9.0 Hz), 6.90 (1H, td, J = 1.8 Hz, 9.4 Hz), 7.11 (1H, d, J = 9.0 Hz), 8.50 (1H, dd, J = 2.7 Hz, 9.0 Hz), 9.02 (1H, d, J = 2.7 Hz). 52

—H —H —H —SO₂CH₃ ¹H NMR (CDCl₃) 1.31 (3H, t, J = 7.1 Hz), 3.17 (3H, s), 4.25 (2H, q, J = 7.1 Hz), 4.47 (2H, s), 7.09 (1H, d, J = 8.9 Hz), 7.20 (2H, d, J = 8.7 Hz), 7.60 (2H, d, J = 8.9 Hz), 8.51 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz). 53

—CH₃ —H —H —SO₂CH₃ ¹H NMR (CDCl₃) 1.31 (3H, t, J = 7.1 Hz), 2.16 (3H, s), 3.17 (3H, s), 4.25 (2H, q, J = 7.1 Hz), 4.46 (2H, s), 7.07 (1H, dd, J = 9.1 Hz, 0.7 Hz), 7.08 (1H, d, J = 7.3 Hz), 7.40 (1H, d, J = 2.6 Hz), 7.44 (1H, dd, J = 7.3 Hz, 2.6 Hz), 8.50 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01 (1H, dd, J = 2.8 Hz. 0.7 Hz). 54 —H —CF₃ —H —H —C₂H₅ MS 291 (M⁺)

TABLE 7

Refer- ence Exam- ple No. R₁₁₉ R₁₂₀ R₁₂₁ ¹H NMR (CDCl₃) δ ppm 55 4-CF₃Ph— —H —H 1.30 (3H, t, J = 7.1 Hz), 3.89 (2H, d, J = 4.6 Hz), 3.95 (2H, s), 4.20 (1H, brs), 4.25 (2H, q, J = 7.1 Hz), 6.62 (2H, d, J = 8.9 Hz), 6.77 (1H, d, J = 8.4 Hz), 6.97 (2H, d, J = 8.9 Hz), 7.27 (2H, d, J = 7.9 Hz), 7.39 (1H, dd, J = 8.4 Hz, 2.5 Hz), 7.54 (2H, d, J = 7.9 Hz), 8.03 (1H, d, J = 2.5 Hz). 56 4-CF₃PhO— —H —SO₂CH₃ 1.30 (3H, t, J = 7.1 Hz), 3.15 (3H, s), 4.23 (2H, q, J = 7.1 Hz), 4.45 (2H, s), 5.06 (2H, s), 6.99-7.04 (3H, m), 7.16 (2H, d, J = 8.9 Hz), 7.54 (2H, d, J = 8.9 Hz), 7.56 (2H, d, J = 9.2 Hz), 7.79-7.83 (1H, m), 8.23 (1H, d, J = 2.0 Hz). 57 4-CF₃PhO— —CH₃ —SO₂CH₃ 1.30 (3H, t, J = 7.1 Hz), 2.19 (3H, s), 3.16 (3H, s), 4.24 (2H, q, J = 7.1 Hz), 4.44 (2H, s), 5.05 (2H, s), 6.96- 7.07 (4H, m), 7.36 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.42 (1H, d, J = 2.3 Hz), 7.56 (2H, d, J = 8.9 Hz), 7.80 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.20 (1H, d, J = 2.3 Hz). (Ph means a benzene ring having 1 to 4 free valences. Hereinafter Ph indicates the same meaning.)

Reference Example 58 t-Butyl (3-cyano-4-hydroxyphenylamino)acetate

MS 248 (M⁺)

Reference Example 59 Production of 2-[4-(2-fluoro-4-nitrophenoxy)phenoxy]-1-(4-piperonylpiperazin-1-yl)ethanone

Potassium carbonate (0.350 g, 2.53 mmol) was added to a solution of 4-(2-fluoro-4-nitrophenoxy)phenol (0.420 g, 1.69 mmol) and 1-chloroacetyl-4-piperonylpiperazine (0.500 g, 1.70 mmol) in DMF (8 mL). The resulting reaction mixture was stirred for 40 minutes at 100° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.860 of the title compound.

Appearance: Brown oil

¹H NMR (CDCl₃) δ 2.50-2.60 (4H, m), 3.43 (2H, s), 3.50-3.70 (4H, m), 4.71 (2H, s), 5.95 (2H, s), 6.65-6.75 (2H, m), 6.80-7.05 (6H, m), 7.94 (1H, dd, J=2.3 Hz, 9.1 Hz), 8.06 (1H, dd, J=2.3 Hz, 10.4 Hz).

The following compound was produced in the same manner as in Reference Example 59.

Reference Example 60 2-(4-(2-fluoro-4-nitrophenoxy)phenylamino]-1-(4-piperonylpiperazin-1-yl)ethanone

¹H NMR (DMSO-d₆) δ 2.25-2.40 (4H, m), 3.43 (2H, s), 3.45-3.50 (4H, m), 3.90 (2H, d, J=5.1 Hz), 5.75 (1H, t, J=5.1 Hz), 5.99 (2H, s), 6.70-6.75 (3H, m), 6.80-7.00 (5H, m), 8.05 (1H, ddd, J=1.4 Hz, 2.7 Hz, 10.5 Hz), 8.27 (1H, dd, J=2.7 Hz, 11.0 Hz).

Reference Example 61 Production of methyl 3-(4-benzyloxyphenylamino)propionate

Under nitrogen, 4-benzyloxyaniline (13.0 g, 65 mmol) was dissolved by heating at 70° C., and a boron trifluoride-diethyl ether complex (0.82 mL, 6.5 mmol) was added dropwise at the same temperature to the dissolved solution. Methyl acrylate (5.85 mL, 65 mmol) was then slowly added dropwise to the resulting solution. This solution was stirred for 10 hours at 70° C. After cooling with ice, ethyl acetate was added to the reaction mixture and washed with aqueous 1 N sodium hydroxide and brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 17.5 g of the title compound.

Appearance: Brown powder

¹H NMR(CDCl₃) δ 2.60 (2H, t, J=6.4 Hz), 3.39 (2H, t, J=6.4 Hz), 3.69 (3H, s), 3.77 (1H, brs), 4.98 (2H, s), 6.58 (2H, d, J=8.9 Hz), 6.85 (2H, d, J=8.9 Hz), 7.30-7.44 (5H, m).

Reference Example 62 Production of ethyl 3-(4-Methoxyphenylamino)propionate

3-(4-hydroxyphenylamino)propionic acid (4.00 g, 20.5 mmol) was added to 48% hydrobromic acid (50 mL), and the resulting solution was stirred for 2.5 hours at 100° C. After concentration under reduced pressure, ethanol (10 mL) was added to the residue, and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 1.27 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.2 Hz), 2.59 (2H, t, J=6.4 Hz), 3.38 (2H, t, J=6.4 Hz), 4.15 (2H, q, J=7.2 Hz), 6.55 (2H, d, J=8.8 Hz), 6.70 (2H, d, J=8.8 Hz).

Reference Example 63

Production of ethyl [(3-fluoro-4-hydroxyphenyl)methylamino]acetate

Ethyl (3-fluoro-4-hydroxyphenylamino)acetate (1.06 g, 5.1 mmol) was dissolved in methanol (150 mL) and the resulting solution was cooled with ice. To the resulting solution were added aqueous 37% formaldehyde (1.5 mL), sodium triacetoxyborohydride (1 g, 16 mmol) and acetic acid (0.9 mL, 15 mmol), and then stirred at room temperature under a nitrogen atmosphere for 14 hours. The solvent was evaporated under reduced pressure. Water was added to the residue, and the resulting solution was neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to the by yield 0.93 g of the title compound.

Appearance: Light brown oil

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7.1 Hz), 3.00 (3H, s), 3.98 (2H, s), 4.17 (2H, q, J=7.1 Hz), 4.68 (1H, brs), 6.31-6.52 (2H, m), 6.87 (1H, t, J=8.9 Hz).

The following compounds were produced in the same manner as in Reference Example 63.

Reference Example 64 Ethyl (methyl{4-[5-(4-trifluoromethylbenzyl)pyridin-2-yloxy]phenyl}amino)acetate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7.1 Hz), 3.07 (3H, s), 3.95 (2H, s), 4.04 (2H, s), 4.18 (2H, q, J=7.1 Hz), 6.69 (2H, d, J=9.1 Hz), 6.75 (1H, d, J=8.5 Hz), 7.00 (2H, d, J=9.1 Hz), 7.27 (2H, d, J=8.1 Hz), 7.39 (1H, dd, J=8.5 Hz, 2.5 Hz), 7.54 (2H, d, J=8.1 Hz), 8.04 (1H, d, J=2.5 Hz).

Reference Example 65 Ethyl [(4-hydroxy-2-trifluoromethylphenyl)methylamino]-acetate

MS 277 (M⁺).

TABLE 8

Reference Example No. R₁₂₂ R₁₂₃ R₁₂₄ R₁₂₅ M ¹H NMR (CDCl₃) δ ppm 66 —H —H —CH₃ —CH₃ 1 3.00 (3H, s), 3.71 (3H, s), 4.01 (2H, s), 4.55 (1H, brs), 6.62 (2H, d, J = 9.2 Hz), 6.75 (2H, d, J = 9.2 Hz). 67 Benzyl —H —CH₃ —CH₃ 2 2.51-2.57 (2H, m), 2.86 (3H, s), 3.56-3.62 (2H, m), 3.66 (3H, s), 5.00 (2H, s), 6.72 (2H, d, J = 9.1 Hz), 6.91 (2H, d, J = 9.1 Hz), 7.30- 7.45 (5H, m). 68 —H —F —C₂H₅ —C₂H₅ 1 1.18 (3H, t, J = 7.1 Hz), 1.26 (3H, t, J = 7.1 Hz), 3.38 (2H, q, J = 7.1 Hz), 3.94 (2H, s), 4.19 (2H, q, J = 7.1 Hz), 4.61 (1H, brs), 6.30-6.35 (1H, m), 6.43 (1H, dd, J = 13.7 Hz, 3.0 Hz), 6.86 (1H, t, J = 8.9 Hz). 69 —H —OCH₃ —C₂H₅ —C₂H₅ 1 1.17 (3H, t, J = 7.1 Hz), 1.25 (3H, t, J = 7.1 Hz), 3.39 (2H, q, J = 7.1 Hz), 3.85 (3H, s), 3.95 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 5.30 (1H, brs), 6.21 (1H, dd, J = 8.6 Hz, 2.8 Hz), 6.33 (1H, d, J = 2.8 Hz), 6.79 (1H, d, J = 8.7 Hz). 70

—CH₃ —C₂H₅ —C₂H₅ 1 1.23 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.1 Hz), 2.08 (3H, s), 3.47 (2H, q, J = 7.1 Hz), 4.01 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.40- 6.59 (2H, m), 6.81-7.00 (2H, m), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz). 71

—CH₃ —CH₃ —C₂H₅ 1 1.27 (3H, t, J = 7.1 Hz), 2.10 (3H, s), 3.08 (3H, s), 4.06 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 6.50- 6.62 (2H, m), 6.85-6.99 (2H, m), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8 Hz). 72

—OCH₃ —CH₃ —C₂H₅ 1 1.27 (3H, t, J = 7.1 Hz), 3.11 (3H, s), 3.74 (3H, s), 4.07 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 6.27 (1H, dd, J = 8.7 Hz, 2.8 Hz), 6.34 (1H, d, J = 2.8 Hz), 6.95-7.01 (2H, m), 8.42 (1H, dd, J = 9.2 Hz, 3.0 Hz), 9.03 (1H, d, J = 2.8 Hz). (M means the number of the methylene groups. Hereinafter M indicates the same meaning.)

TABLE 9

Reference Example No. R₁₂₆ R₁₂₇ ¹H NMR (CDCl₃) δ ppm 73 —H —CH₃ 2.41 (4H, brs), 2.88 (3H, s), 3.42 (2H, s), 3.50 (2H, brs), 3.60 (2H, brs), 3.94 (2H, s), 5.92 (2H, s), 6.55-6.69 (4H, m), 6.72 (2H, s), 6.82 (1H, s), 7.47 (1H, brs). 74 —H —C₂H₅ 1.05 (3H, t, J = 7.1 Hz), 2.44 (4H, brs), 3.25 (2H, q, J = 7.1 Hz), 3.46 (2H, s), 3.60 (4H, brs), 3.91 (2H, s), 5.94 (2H, s), 6.63 (4H, s), 6.72-6.74 (2H, m), 6.82 (1H, s), 7.43 (1H, brs). 75

—CH₃ 2.44 (4H, brs), 3.06 (3H, s), 3.44 (2H, s), 3.49 (2H, brs), 3.63 (2H, brs), 4.11 (2H, s), 5.94 (2H, s), 6.69-6.77 (4H, m), 6.85 (1H, s), 6.92-7.02 (3H, m), 8.41 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 3.0 Hz). 76

—C₂H₅ 1.20 (3H, t, J = 7.1 Hz), 2.42-2.46 (4H, m), 3.44-3.51 (6H, m), 3.64 (2H, q, J = 7.1 Hz), 4.06 (2H, s), 5.95 (2H, s), 6.67 (2H, d, J = 9.2 Hz), 6.74 (2H, brs), 6.85 (1H, brs), 6.94 (1H, d, J = 9.1 Hz), 6.99 (2H, d, J = 9.1 Hz), 8.42 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8 Hz).

Reference Example 77 Production of 1-(4-piperonylpiperazin-1-yl]-2-[cyclopropyl(4-hydroxyphenyl)amino]ethanone

To a solution of 1-(4-piperonylpiperazin-1-yl)-2-(4-hydroxyphenylamino)ethanone (1.00 g, 2.7 mmol) in methanol (10 mL) were added acetic acid (1.55 mL, 27 mmol), molecular sieves 3A1/16 (1.00 g), [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.653 mL, 3.2 mmol) and sodium cyanoborohydride (770 mg, 12 mmol). The resulting solution was stirred for 16 hours at 60° C. This reaction solution was filtered and concentrated, and to the residue were added ethyl acetate and water. The aqueous layer was adjusted to pH 10 using aqueous 6 N sodium hydroxide. This layer was stirred for some time, and once insoluble matter had dissolved, the ethyl acetate layer was removed, and washed with aqueous 2 N sodium hydroxide and a saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 770 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 0.54-0.59 (2H, m), 0.72-0.79 (2H, m), 2.39-2.45 (4H, m), 2.70-2.77 (1H, m), 3.44 (2H, s), 3.48-3.51 (2H, m), 3.57-3.60 (2H, m), 4.12 (2H, s), 5.95 (2H, s), 6.62-6.67 (2H, m), 6.74-6.85 (5H, m).

The following compound was produced in the same manner as in Reference Example 77.

Reference Example 78 Ethyl {cyclopropyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetate

¹H NMR (CDCl₃) δ 0.66-0.72 (2H, m), 0.83-0.89 (2H, m), 1.26 (3H, t, J=7.3 Hz), 2.10 (3H, s), 2.71-2.79 (1H, m), 4.08-4.22 (4H, m), 6.77-6.82 (2H, m), 6.91-6.95 (2H, m), 8.40-8.45 (1H, m), 9.05 (1H, d, J=2.8 Hz).

Reference Example 79 Production of ethyl [(3-hydroxyphenyl)methylamino]-acetate

Potassium bicarbonate (1.42 mL, 14.19 mmol) was added to a solution of ethyl (3-hydroxyphenylamino)acetate (2.77 g, 14.19 mmol) in DMF (15 mL). To the resulting solution was further added methyl iodide (1.77 mL, 28.38 mmol), and then stirred at room temperature for 18 hours. To the resulting reaction solution was added brine (150 mL), and the obtained mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, after which solvent was evaporated, to thereby yield 2.48 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7.1 Hz), 3.04 (3H, s), 4.03 (2H, s), 4.18 (2H, q, J=7.1 Hz), 5.17 (1H, brs), 6.17-6.27 (3H, m), 7.04-7.10 (1H, m).

The following compounds were produced in the same manner as in Reference Example 79.

TABLE 10

Reference Example No. R₁₂₈ R₁₂₉ R₁₃₀ R₁₃₁ ¹H NMR (CDCl₃) δ ppm or MS 80 —H —H —H

¹H NMR 1.22 (3H, t, J = 7.1 Hz), 1.43 (3H, d, J = 7.1 Hz), 2.83 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 4.33 (1H, q, J = 7.1 Hz), 4.84 (1H, brs), 6.75 (4H, s). 81 —CH₃ —H —H

¹H NMR 1.23 (3H, t, J = 7.3 Hz), 1.42 (3H, d, J = 7.1 Hz), 2.22 (3H, s), 2.82 (3H, s), 4.08-4.21 (2H, m), 4.30 (1H, s), 4.33 (1H, q, J = 7.1 Hz), 6.58 (1H, dd, J = 8.6 Hz, 3.0 Hz), 6.65 (1H, d, J = 2.8 Hz), 6.68 (1H, d, J = 8.6 Hz). 82 —OCH₃ —H —H

¹H NMR 1.17 (3H, t, J = 7.1 Hz), 3.39 (2H, q, J = 7.1 Hz), 3.75 (3H, s), 4.00 (2H, brs), 5.11 (1H, brs), 5.15 (2H, s), 6.21 (1H, dd, J = 8.6 Hz, 2.8 Hz), 6.27 (1H, d, J = 2.8 Hz), 6.77 (1H, d, J = 8.6 Hz), 7.27-7.37 (5H, m). 83 —F —H —F

¹H NMR 1.24 (3H, t, J = 7.1 Hz), 2.92 (3H, s), 3.93 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 4.96 (1H, d, J = 2.8 Hz), 6.70 (1H, d, J = 8.2 Hz, 12.9 Hz), 6.77 (1H, d, J = 8.1 Hz, 12.2 Hz). 84 —CH₃ —H —CH₃

¹H NMR 0.99 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.1 Hz), 2.18 (3H, s), 2.24 (3H, s), 3.10 (2H, q, J = 7.1 Hz), 3.68 (2H, s), 4.11 (2H, q, J = 7.1 Hz), 4.47 (1H, s), 6.59 (1H, s), 6.94 (1H, s). 85 —H —H —H

¹H NMR 1.26 (3H, t, J = 7.3 Hz), 1.33 (6H, s), 2.80 (3H, s), 4.18 (2H, q, J = 7.3 Hz), 5.15 (1H, brs), 6.71 (2H, d, J = 8.9 Hz), 7.00 (2H, d, J = 8.9 Hz). 86 —H —CH₃ —CH₃

MS 237 (M⁺) 87 —CH₃ —H —CH₃

¹H NMR 1.24 (3H, t, J = 7.1 Hz), 2.19 (3H, s), 2.24 (3H, s), 2.79 (3H, s), 3.64 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 4.45 (1H, brs), 6.59 (1H, s), 6.89 (1H, s). 88 —CF₃ —H —H

MS 277 (M⁺) 89 —CN —H —H

MS 262 (M⁺)

TABLE 11

Reference Example No. R₁₃₂ R₁₃₃ R₁₃₄ R₁₃₅ R₁₃₆ M ¹H NMR (CDCl₃) δ ppm 90 —H —H —H —C₂H₅ —C₂H₅ 1 1.24 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.0 Hz), 3.48 (2H, q, J = 7.1 Hz), 4.02 (2H, s), 4.21 (2H, q, J = 7.0 Hz), 6.67 (2H, d, J = 8.9 Hz), 6.95 (1H, d, J = 9.1 Hz), 7.00 (2H, d, J = 8.9 Hz), 8.42 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.06 (1H, d, J = 2.8 Hz). 91 —H —H —H —CH₃ —C₂H₅ 1 1.27 (3H, t, J = 7.2 Hz), 3.10 (3H, s), 4.07 (2H, s), 4.20 (2H, q, J = 7.2 Hz), 6.71 (2H, d, J = 9.2 Hz), 6.95 (1H, d, J = 9.1 Hz), 7.02 (2H, d, J = 9.2 Hz), 8.43 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.05 (1H, d, J = 2.8 Hz). 92 —F —H —H allyl —C₂H₅ 1 1.29 (3H, t, J = 7.1 Hz), 4.02 (4H, brs), 4.23 (2H, q, J = 7.1 Hz), 5.21-5.30 (2H, m), 5.84-5.94 (1H, m), 6.40-6.52 (2H, m), 7.01-7.08 (2H, m), 8.47 (1H, dd, J = 8.9 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.6 Hz). 93 —F —H —F —C₂H₅ —C₂H₅ 1 1.22 (3H, t, J = 7.1 Hz), 1.27 (3H, t, J = 7.1 Hz), 3.37 (2H, q, J = 7.1 Hz), 4.02 (2H, s), 4.20 (2H, q, J = 7.1 Hz), 6.77 (1H, dd, J = 8.1 Hz, 12.3 Hz), 6.92 (1H, dd, J = 7.3 Hz, 12.7 Hz), 7.09 (1H, d, J = 9.0 Hz), 8.49 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.02 (1H, d, J = 2.8 Hz). 94 —F —F —H —CH₃ —C(CH₃)₃ 0 1.45 (9H, s), 3.26 (3H, s), 6.90-7.11 (2H, m), 7.16 (1H, d, J = 9.0 Hz), 8.53 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.01 (1H, d, J = 2.8 Hz).

TABLE 12

Reference Example No. R₁₃₇ R₁₃₈ R₁₃₉ Xa₃ Xa₄ ¹H NMR (CDCl₃) δ ppm 95

—H piperonyl none —CH₂— 2.44 (8H, brs), 2.96 (2H, s), 3.30 (3H, s), 3.38 (2H, s), 5.92 (2H, s), 6.72 (2H, brs), 6.82 (1H, s), 7.09 (1H, d, J = 9.1 Hz), 7.20 (2H, d, J = 8.9 Hz), 7.29 (2H, d, J = 8.9 Hz), 8.51 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz). 96

—H benzyl none none 1.55-1.80 (3H, m), 1.81- 2.15 (3H, m), 2.23 (4H, t, J = 5.0 Hz), 3.16 (3H, s), 3.20 (4H, t, J = 5.0 Hz), 3.42 (2H, s), 3.55-3.69 (1H, m), 3.85-4.00 (1H, m), 5.36 (1H, t, J = 3.2 Hz), 6.99 (4H, s), 7.16-7.36 (5H, m). 97 —H —CH₃ piperonyl —CH₂— none 2.18 (3H, s), 2.38-2.42 (4H, m), 2.89 (3H, s), 3.41 (2H, s), 3.50 (2H, brs), 3.61 (2H, brs), 3.95 (2H, brs), 5.93 (2H, s), 6.44-6.57 (3H, m), 6.73- 6.76 (2H, m), 6.83 (1H, s).

TABLE 13

Reference Example No. R₁₄₀ ¹H NMR (CDCl₃) δ ppm 98 —NO₂ 1.07 (3H, t, J = 7.1 Hz), 2.15 (3H, s), 3.38 (3H, s), 4.19 (2H, q, J = 7.1 Hz), 7.06-7.20 (4H, m), 8.51 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.97 (1H, d, J = 2.8 Hz). 99 4-CF₃PhOCH₂— 1.07 (3H, t, J = 7.1 Hz), 2.18 (3H, s), 3.36 (3H, s), 4.08 (2H, q, J = 7.1 Hz), 5.04 (2H, s), 6.97 (1H, d, J = 8.6 Hz), 7.01-7.13 (4H, m), 7.16 (1H, d, J = 2.3 Hz), 7.57 (2H, d, J = 8.6 Hz), 7.80 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.17 (1H, d, J = 2.3 Hz).

Reference Example 100 Production of ethyl [acetyl(3-fluoro-4-hydroxyphenyl)amino]acetate

Ethyl (3-fluoro-4-hydroxyphenylamino)acetate (0.84 g, 4 mmol) was dissolved in N,N-dimethylacetamide (4 mL). To the resulting solution was added acetyl chloride (0.6 mL, 10 mmol), and the resulting solution was stirred at room temperature for 1 hour. Water (1 mL), methanol (10 mL) and saturated sodium carbonate (10 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the solution. 10% hydrochloric acid was employed to turn the solution acidic, and then the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1), to thereby yield 0.84 g of the title compound.

Appearance: Colorless powder

¹H NMR (CDCl₃) δ 1.28 (3H, t, J=7.3 Hz), 1.94 (3H, s), 4.20 (2H, q, J=7.3 Hz), 4.32 (2H, s), 6.02 (1H, brs), 6.99-7.07 (2H, m), 7.13-7.18 (1H, m).

The following compounds were produced in the same manner as in Reference Example 100.

TABLE 14

Reference Example No. R₁₄₁ R₁₄₂ M ¹H NMR (CDCl₃) δ ppm 101 —H —CH₃ 1 1.26 (3H, t, J = 7.1 Hz), 1.92 (3H, s), 2.24 (3H, s), 4.19 (2H, q, J = 7.1 Hz), 4.32 (2H, s), 5.38 (1H, brs), 6.78 (1H, d, J = 8.4 Hz), 7.04 (1H, dd, J = 8.4 Hz, 2.5 Hz), 7.10 (1H, d, J = 2.5 Hz). 102 —H —H 2 1.21 (3H, t, J = 7.2 Hz), 1.83 (3H, s), 2.56 (2H, t, J = 7.4 Hz), 3.97 (2H, t, J = 7.4 Hz), 4.06 (2H, q, J = 7.2 Hz), 6.05 (1H, brs), 6.87 (2H, d, J = 8.7 Hz), 7.03 (2H, d, J = 8.7 Hz). 103 benzyl —H 1 1.26 (3H, t, J = 7.1 Hz), 1.91 (3H, s), 4.18 (2H, q, J = 7.1 Hz), 4.33 (2H, s), 5.07 (2H, s), 6.98 (2H, d, J = 8.9 Hz), 7.26 (2H, d, J = 8.9 Hz), 7.35-7.45 (5H, m). 104

—H 1 1.24 (3H, t, J = 7.1 Hz), 1.89 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 4.32 (2H, s), 6.95 (2H, d, J = 8.9 Hz), 7.12 (1H, t, J = 9.0 Hz), 7.27-7.32 (3H, m), 7.52- 7.60 (1H, m), 7.70-7.80 (2H, m), 7.99 (1H, s), 8.05 (1H, s).

TABLE 15

Reference Example No. R₁₄₃ ¹H NMR (CDCl₃) δ ppm 105 —C₂H₅ 1.09 (3H, t, J = 7.4 Hz), 2.20 (2H, q, J = 7.4 Hz), 2.40-2.45 (4H, m), 3.43 (4H, brs), 3.61 (2H, brs), 4.47 (2H, s), 5.94 (2H, s), 6.70-6.76 (2H, m), 6.84 (1H, s), 7.08 (1H, d, J = 9.0 Hz), 7.19 (2H, d, J = 8.7 Hz), 7.52 (2H, d, J = 8.7 Hz), 8.51 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.04 (1H, d, J = 2.8 Hz). 106 —CH₂Cl 2.40-2.48 (4H, m), 3.43 (4H, s), 3.62 (2H, brs), 3.97 (2H, s), 4.49 (2H, s), 5.95 (2H, s), 6.70-6.77 (2H, m), 6.84 (1H, s), 7.11 (1H, d, J = 9.0 Hz), 7.23 (2H, d, J = 8.7 Hz), 7.59 (2H, d, J = 8.7 Hz), 8.52 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.04 (1H, d, J = 2.8 Hz). 107 cyclopropyl 0.65-1.52 (5H, m), 2.43 (4H, brs), 3.43 (4H, brs), 3.61 (2H, brs), 4.50 (2H, brs), 5.95 (2H, s), 6.72- 6.75 (2H, m), 6.84 (1H, s), 7.08 (1H, d, J = 9.1 Hz), 7.20 (1H, d, J = 8.8 Hz), 7.59 (2H, d, J = 8.8 Hz), 8.50 (1H, dd, J = 2.9 Hz, 9.1 Hz), 9.04 (1H, d, J = 2.9 Hz).

TABLE 16

Reference Example No. R₁₄₄ ¹H NMR (CDCl₃) δ ppm 108 —H 1.44 (3H, t, J = 7.1 Hz), 4.43 (2H, q, J = 7.1 Hz), 5.05 (2H, s), 6.93 (1H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.9 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.69 (2H, d, J = 8.9 Hz), 7.79 (1H, dd, J = 8.4 Hz, 2.5 Hz), 8.22 (1H, d, J = 2.5 Hz), 8.90 (1H, brs). 109 —CH₃ 1.44 (3H, t, J = 7.1 Hz), 2.19 (3H, s), 4.43 (2H, q, J = 7.1 Hz), 5.03 (2H, s), 6.94 (1H, d, J = 8.4 Hz), 7.02 (2H, d, J = 8.4 Hz), 7.07 (1H, d, J = 8.6 Hz), 7.51-7.58 (4H, m), 7.78 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.20 (1H, d, J = 2.5 Hz), 8.84 (1H, brs).

Reference Example 110 Production of (6-chloropyridin-3-yl) (4-trifluoromethylphenyl)methanone

Under an argon gas flow, half of a solution of 4-bromobenzotrifluoride (1.20 g, 5.33 mmol) in THF (6 mL) was added to magnesium (156 mg, 6.41 mmol). The resulting solution was stirred, and further 1,2-dibromoethane (3 drops) was added. Once the reaction began, the balance of the 4-bromobenzotrifluoride in THF solution was added dropwise, and once dropping had finished, the resulting solution was stirred for 30 minutes at 60° C. A solution of 6-chloro-N-methoxy-N-methylnicotinamide (990 mg, 5.36 mmol) in THF (3 mL) was charged into a separate reaction vessel, into which the above reaction solution was added dropwise under an argon gas flow and ice cooling. After dropping had finished, the resulting solution was stirred for 30 minutes at room temperature, and then heated to reflux for 1 hour. The reaction solution was cooled with ice, then aqueous ammonium chloride and water were added. The resulting solution was extracted with ethyl acetate, and washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 610 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 7.52 (1H, d, J=8.3 Hz), 7.80 (2H, d, J=8.0 Hz), 7.90 (2H, d, J=8.0 Hz), 8.11 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.77 (1H, d, J=2.0 Hz).

Reference Example 111 Production of ethyl 3-[4-(4-nitrophenoxy)phenyl]-propionate

To a solution of ethyl 3-(4-hydroxyphenyl)propionate (6.00 g, 30.9 mmol) in DMF (60 mL) were added 4-fluoronitrobenzene (6.54 g, 46.3 mmol) and potassium carbonate (5.12 g, 37.1 mmol). The resulting reaction solution was stirred for 1 hour at 80° C. To the reaction solution was added water and extracted with ethyl acetate. The resulting ethyl acetate layer was washed with water and then with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 9.64 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7.1 Hz), 2.62 (2H, t, J=7.7 Hz), 2.96 (2H, t, J=7.7 Hz), 4.12 (2H, q, J=7.1 Hz), 6.93-7.06 (4H, m), 7.24 (2H, d, J=8.5 Hz), 8.17 (2H, d, J=9.2 Hz).

The following compounds were produced in the same manner as in Reference Example 111.

TABLE 17

Reference Example No. R₁₄₅ ¹H NMR (solvent) δ ppm 112 —Ac (DMSO-d₆) 2.58 (3H, s), 7.26 (2H, d, J = 8.8 Hz), 7.40 (1H, t, J = 8.4 Hz), 8.04 (2H, d, J = 8.8 Hz), 8.15 (1H, ddd, J = 1.4 Hz, 2.6 Hz, 8.4 Hz), 8.39 (1H, dd, J = 2.6 Hz, 10.7 Hz). 113 —CH₂COOCH₃ (DMSO-d₆) 3.63 (3H, s), 3.72 (2H, s), 7.11-7.17 (3H, m), 7.38 (2H, d, J = 8.4 Hz), 8.09 (1H, ddd, J = 1.4 Hz, 2.7 Hz, 9.1 Hz), 8.33 (1H, dd, J = 2.7 Hz, 10.2 Hz). 114 —(CH₂)₂COOC₂H₅ (CDCl₃) 1.22 (3H, t, J = 7.1 Hz), 2.62 (2H, t, J = 7.6 Hz), 2.96 (2H, t, J = 7.6 Hz), 4.12 (2H, q, J = 7.1 Hz), 6.92 (1H, dd, J = 9.0 Hz, 8.0 Hz), 6.99 (2H, d, J = 8.6 Hz), 7.24 (2H, d, J = 8.6 Hz), 7.90-8.00 (1H, m), 8.06 (1H, dd, J = 10.3 Hz, 2.7 Hz). 115 —NHAc (DMSO-d₆) 2.05 (3H, s), 7.07 (1H, t, J = 8.6 Hz), 7.16 (2H, d, J = 9.0 Hz), 7.67 (2H, d, J = 9.0 Hz), 8.06 (1H, ddd, J = 1.4 Hz, 2.7 Hz, 8.6 Hz), 8.31 (1H, dd, 2.7 Hz, 10.9 Hz), 10.06 (1H, s). 116 —SCH₂COOC₂H₅ (CDCl₃) 1.24 (3H, t, J = 7.1 Hz), 3.62 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 6.95- 7.05 (3H, m), 7.49 (2H, d, J = 8.8 Hz), 8.00 (1H, ddd, J = 1.5 Hz, 2.6 Hz, 9.1 Hz), 8.08 (1H, dd, J = 2.6 Hz, 10.2 Hz). 117 —OCH₃ (DMSO-d₆) 3.77 (3H, s), 6.90-7.10 (3H, m), 7.16 (2H, d, J = 9.1 Hz), 8.03 (1H, ddd, J = 1.4 Hz, 2.6 Hz, 9.2 Hz), 8.27 (1H, dd, J = 2.6 Hz, 10.9 Hz). 118 —H (CDCl₃) 6.95 (1H, dd, J = 9.0 Hz, 8.0 Hz), 7.07 (2H, d, J = 7.9 Hz), 7.24 (2H, t, J = 7.9 Hz), 7.42 (2H, t, J = 7.9 Hz), 7.91-8.02 (1H, m), 8.07 (1H, dd, J = 10.3 Hz, 2.7 Hz). 119 —(CH₂)₃COOC₂H₅ (CDCl₃) 1.25 (3H, t, J = 7.1 Hz), 1.88- 2.03 (2H, m), 2.32 (2H, t, J = 7.4 Hz), 2.66 (2H, t, J = 7.4 Hz), 4.12 (2H, q, J = 7.1 Hz), 6.91 (1H, dd, J = 9.0 Hz, 8.0 Hz), 6.99 (2H, d, J = 8.5 Hz), 7.22 (2H, d, J = 8.5 Hz), 7.91-7.98 (1H, m), 8.06 (1H, dd, J = 10.3 Hz, 2.7 Hz) 120 —CHO (DMSO-d₆) 7.33 (2H, d, J = 8.7 Hz), 7.47 (1H, t, J = 9.0 Hz), 8.00 (2H, d, J = 8.7 Hz), 8.16 (1H, ddd, J = 1.4 Hz, 2.7 Hz, 9.0 Hz), 8.40 (1H, dd, J = 2.7 Hz, 10.6 Hz), 9.99 (1H, s). 121 —COOC₂H₅ (DMSO-d₆) 1.32 (3H, t, J = 7.1 Hz), 4.31 (2H, q, J = 7.1 Hz), 7.26 (2H, d, J = 8.9 Hz), 7.41 (1H, t, J = 8.4 Hz), 8.03 (2H, d, J = 8.9 Hz), 8.14 (1H, ddd, J = 1.4 Hz, 2.6 Hz, 8.4 Hz), 8.39 (1H, dd, J = 2.6 Hz, 10.6 Hz). (Ac means an acetyl group. Hereinafter Ac indicates the same meaning.)

TABLE 18

Reference Example No. R₁₄₆ R₁₄₇ ¹H NMR (solvent) δ ppm 122 4-NO₂

(DMSO-d₆) 1.33 (3H, t, J = 7.1 Hz), 4.32 (2H, q, J = 7.1 Hz), 7.24-7.31 (4H, m), 8.05 (2H, d, J = 8.9 Hz), 8.29 (2H, d, J = 9.3 Hz). 123 4-NO₂

(CDCl₃) 3.10 (3H, s), 3.75 (3H, s), 4.10 (2H, s), 6.71 (2H, d, J = 9.2 Hz), 6.96 (2H, d, J = 9.2 Hz), 6.98 (2H, d, J = 9.2 Hz), 8.17 (2H, d, J = 9.2 Hz). 124 2-NO₂

(CDCl₃) 1.22 (3H, t, J = 7.1 Hz), 2.60 (2H, t, J = 7.7 Hz), 2.93 (2H, t, J = 7.7 Hz), 4.11 (2H, q, J = 7.1 Hz), 6.92- 6.99 (3H, m), 7.13-7.23 (3H, m), 7.45 (1H, dt, J = 1.6 Hz, 8.2 Hz), 7.92 (1H, dd, J = 8.2 Hz, 1.6 Hz). 125 4-NO₂

(CDCl₃) 1.50 (9H, s), 2.53 (2H, brs), 3.66 (2H, m), 4.10 (2H, brs), 6.05 (1H, brs), 7.02 (2H, d, J = 9.0 Hz), 7.06 (2H, d, J = 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz), 8.21 (2H, d, J = 8.0 Hz). 126 4-NO₂

(CDCl₃) 1.21 (3H, t, J = 7.1 Hz), 2.61 (2H, t, J = 7.7 Hz), 2.95 (2H, t, J = 7.7 Hz), 4.10 (2H, q, J = 7.1 Hz), 6.88- 6.94 (2H, m), 6.98 (2H, d, J = 9.2 Hz), 7.08 (1H, d, J = 7.6 Hz), 7.32 (1H, t, J = 7.6 Hz), 8.18 (2H, d, J = 9.2 Hz). 127 4-NO₂

(CDCl₃) 2.58 (2H, t, J = 7.7 Hz), 2.87 (2H, t, J = 7.7 Hz), 3.62 (3H, s), 6.89-7.01 (3H, m), 7.13-7.37 (3H, m), 8.18 (2H, d, J = 9.2 Hz).

TABLE 19

Refer- ence Exam- ple No. R₁₄₈ R₁₄₉ R₁₅₀ ¹H NMR (CDCl₃) δ ppm 128 —H —H —C₂H₅ 1.41 (3H, t, J = 7.3 Hz), 4.40 (2H, q, J = 7.3 Hz), 7.09 (1H, d, J = 8.9 Hz), 7.22-7.26 (2H, m), 8.14-8.17 (2H, m), 8.52 (1H, dd, J = 8.9 Hz, 3.0 Hz), 9.04 (1H, d, J = 3.0 Hz). 129 —H —H —CH₃ 3.94 (3H, s), 7.10 (1H, d, J = 8.9 Hz), 7.22-7.26 (2H, m), 8.13-8.16 (2H, m), 8.52 (1H, dd, J = 8.9 Hz, 2.7 Hz), 9.04 (1H, d, J = 2.7 Hz). 130 —F —H —CH₃ 3.95 (3H, s), 7.18 (1H, d, J = 8.8 Hz), 7.29-7.35 (1H, m), 7.87- 7.96 (2H, m), 8.54 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.99 (1H, d, J = 2.6 Hz). 131 —F —H —C₂H₅ 1.41 (3H, t, J = 7.1 Hz), 4.41 (2H, q, J = 7.1 Hz), 7.18 (1H, d, J = 9.1 Hz), 7.29-7.35 (1H, m), 7.88-7.96 (2H, m), 8.54 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.99 (1H, d, J = 2.8 Hz). 132 —CH₃ —H —CH₃ 2.21 (3H, s), 3.93 (3H, s), 7.08- 7.15 (2H, m), 7.97 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.02 (1H, d, J = 2.2 Hz), 8.52 (1H, dd, J = 8.9 Hz, 2.7 Hz), 9.01 (1H, d, J = 2.7 Hz). 133 —OCH₃ —H —C₂H₅ 1.41 (3H, t, J = 7.1 Hz), 3.80 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 7.09 (1H, d, J = 8.9 Hz), 7.21 (1H, d, J = 8.2 Hz), 7.71-7.77 (2H, m), 8.49 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.97 (1H, d, J = 2.8 H). 134 —H —OCH₃ —CH₃ 3.90 (3H, s), 3.91 (3H, s), 6.77- 6.81 (2H, m), 7.11 (1H, dd, J = 9.1 Hz, 0.5 Hz), 7.91-7.95 (1H, m), 8.53 (1H, dd, J = 9.1 Hz, 2.7 Hz), 9.06 (1H, d, J = 2.7 Hz). 135 —H —CH₃ —CH₃ 2.64 (3H, s), 3.91 (3H, s), 7.02- 7.10 (3H, m), 8.03-8.06 (1H, m), 8.52 (1H, dd, J = 8.9 Hz, 2.7 Hz), 9.05 (1H, dd, J = 2.7 Hz, 0.5 Hz). 136 —Cl —H —CH₃ 3.95 (3H, s), 7.17-7.20 (1H, m), 7.31 (1H, d, J = 8.6 Hz), 8.03- 8.07 (1H, m), 8.20 (1H, d, J = 2.0 Hz), 8.55 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.98 (1H, dd, J = 2.8 Hz, 0.5 Hz). 137 —F —F —CH₃ 3.97 (3H, s), 7.06-7.16 (1H, m), 7.21 (1H, dd, J = 0.3 Hz, 9.0 Hz), 7.77-7.88 (1H, m), 8.56 (1H, dd, J = 2.8 Hz, 9.0 Hz), 8.99 (1H, dd, J = 0.3 Hz, 2.8 Hz)

TABLE 20

Refer- ence Exam- ple No. R₁₅₁ R₁₅₂ M ¹H NMR (CDCl₃) δ ppm 138 —H —CH₃ 2 2.64-2.70 (2H, m), 2.97-3.02 (2H, m), 3.69 (3H, s), 7.01-7.10 (3H, m), 7.26- 7.30 (2H, m), 8.47 (1H, dd, J = 8.9 Hz, 2.6 Hz), 9.04 (1H, d, J = 2.6 Hz). 139 —OCH₃ —C₂H₅ 2 1.26 (3H, t, J = 7.1 Hz), 2.67 (2H, t, J = 7.5 Hz), 2.99 (2H, t, J = 7.5 Hz), 3.74 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 6.76-6.91 (2H, m), 7.02 (1H, d, J = 9.1 Hz), 7.06 (1H, d, J = 8.0 Hz), 8.45 (1H, dd, J = 9.1 Hz, 2.6 Hz), 9.01 (1H, d, J = 2.6 Hz). 140 —H —CH₃ 1 3.67 (2H, s), 3.72 (3H, s), 7.04 (1H, d, J = 8.9 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz), 8.45- 8.50 (1H, m), 9.04 (1H, d, J = 3.0 Hz). 141 —H —C₂H₅ 2 1.23 (3H, t, J = 7.1 Hz), 2.63 (2H, t, J = 7.8 Hz), 2.97 (2H, t, J = 7.8 Hz), 4.11 (2H, q, J = 7.1 Hz), 7.00 (1H, d, J = 9.1 Hz), 7.06 (2H, d, J = 8.5 Hz), 7.26 (2H, d, J = 8.5 Hz), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02 (1H, d, J = 2.8 Hz). 142 —OCH₃ —CH₃ 2 2.66-2.71 (2H, m), 2.97-3.02 (2H, m), 3.70 (3H, s), 3.74 (3H, s), 6.83- 6.88 (2H, m), 7.01-7.08 (2H, m), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01 (1H, d, J = 2.8 Hz). 143 —OC₂H₅ —C₂H₅ 2 1.15 (3H, t, J = 7.0 Hz), 1.26 (3H, t, J = 7.1 Hz), 2.53-2.72 (2H, m), 2.87-3.05 (2H, m), 3.98 (2H, q, J = 7.0 Hz), 4.15 (2H, q, J = 7.1 Hz), 6.73-6.93 (2H, m), 7.02 (1H, d, J = 9.0 Hz), 7.07 (1H, d, J = 8.0 Hz), 8.45 (1H, dd, J = 9.0 Hz, 2.8 Hz), 9.01 (1H, d, J = 2.8 Hz). 144 —F —C₂H₅ 2 1.26 (3H, t, J = 7.1 Hz), 2.57-2.71 (2H, m), 2.89-3.06 (2H, m), 4.15 (2H, q, J = 7.1 Hz), 6.98-7.21 (4H, m), 8.50 (1H, dd, J = 9.0 Hz, 2.8 Hz), 9.01 (1H, d, J = 2.8 Hz). 145 —H —C₂H₅ 4 1.26 (3H, t, J = 7.3 Hz), 1.60-1.80 (4H, m), 2.30-2.40 (2H, m), 2.60- 2.75 (2H, m), 4.13 (2H, q, J = 7.3 Hz), 7.01 (1H, d, J = 9.0 Hz), 7.06 (2H, d, J = 8.6 Hz), 7.25 (2H, d, J = 8.6 Hz), 8.46 (1H, dd, J = 9.0 Hz, 3.0 Hz), 9.04 (1H, d, J = 3.0 Hz).

TABLE 21

Reference Example No. R₁₅₃ R₁₅₄ M ¹H NMR (CDCl₃) δ ppm or MS 146 —CH₃ —H 1 ¹H NMR 1.32 (3H, t, J = 7.1 Hz), 2.08 (3H, s), 3.90 (2H, d, J = 5.3 Hz), 4.15- 4.39 (3H, m), 6.39-6.59 (2H, m), 6.81- 7.01 (2H, m), 8.44 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, dd, J = 2.8 Hz, 0.4 Hz). 147 —CH₃ —Ac 1 ¹H NMR 1.29 (3H, t, J = 7.1 Hz), 1.99 (3H, s), 2.17 (3H, s), 4.22 (2H, q, J = 7.1 Hz), 4.38 (2H, s), 7.05-7.12 (2H, m), 7.22-7.28 (2H, m), 7.31 (1H, s), 8.50 (1H, d, J = 9.0 Hz), 9.01 (1H, s). 148 —H —H 1 ¹H NMR 1.32 (3H, t, J = 7.1 Hz), 3.91 (2H, d, J = 5.4 Hz), 4.27 (2H, q, J = 7.1 Hz), 4.37 (1H, t, J = 5.4 Hz), 6.66 (2H, d, J = 8.9 Hz), 6.96 (1H, d, J = 9.1 Hz), 6.98 (2H, d, J = 8.9 Hz), 8.43 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.05 (1H, d, J = 2.8 Hz). 149 —H —Ac 2 ¹H NMR 1.23 (3H, t, J = 7.1 Hz), 1.90 (3H, s), 2.62 (2H, t, J = 7.3 Hz), 4.03 (2H, t, J = 7.3 Hz), 4.08 (2H, q, J = 7.1 Hz), 7.10 (1H, d, J = 9.0 Hz), 7.21- 7.28 (4H, m), 8.52 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.04 (1H, d, J = 2.8 Hz). 150 —F —C₂H₅ 1 ¹H NMR 1.21-1.32 (6H, m), 3.47 (2H, q, J = 7.1 Hz), 4.01 (2H, s), 4.23 (2H, q, J = 7.1 Hz), 6.38-6.49 (2H, m), 7.01-7.07 (2H, m), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz). 151 —OCH₃ —C₂H₅ 1 ¹H NMR 1.25 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.1 Hz), 3.50 (2H, q, J = 7.1 Hz), 3.72 (3H, s), 4.03 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.23 (1H, dd, J = 8.9 Hz, 2.8 Hz), 6.30 (1H, d, J = 2.6 Hz), 6.95-6.99 (2H, m), 8.42 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz). 152 —F —CH₃ 1 ¹H NMR 1.28 (3H, t, J = 7.1 Hz), 3.09 (3H, s), 4.06 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 6.42-6.54 (2H, m), 7.03-7.10 (2H, m), 8.47 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz). 153 —OCH₃ —H 1 ¹H NMR 1.32 (3H, t, J = 7.1 Hz), 3.72 (3H, s), 3.92 (2H, d, J = 5.3 Hz), 4.27 (2H, q, J = 7.1 Hz), 4.41 (1H, brt), 6.19 (1H, dd, J = 8.4 Hz, 2.5 Hz), 6.29 (1H, d, J = 2.5 Hz), 6.96-7.00 (2H, m), 8.42 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz). 154 —F —Ac 1 ¹H NMR 1.30 (3H, t, J = 7.1 Hz), 2.02 (3H, s), 4.23 (2H, q, J = 7.1 Hz), 4.38 (2H, s), 7.16-7.33 (4H, m), 8.54 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01 (1H, dd, J = 2.8 Hz, 0.5 Hz). 155 —F —H 1 ¹H NMR 1.32 (3H, t, J = 7.1 Hz), 3.89 (2H, d, J = 5.3 Hz), 4.28 (2H, q, J = 7.1 Hz), 4.35-4.55 (1H, m), 6.31-6.50 (2H, m), 6.91-7.11 (2H, m), 8.47 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02 (1H, dd, J = 2.8 Hz, 0.4 Hz). 156 —CF₃ —CH₃ 1 MS 399 (M⁺) 157 —CF₃ —C₂H₅ 1 MS 413 (M⁺)

TABLE 22

Reference Example No. R₁₅₅ R₁₅₆ R₁₅₇ R₁₅₈ R₁₅₉ M ¹H NMR or MS 158 —H —H —H —CH₃ —CH₃ 1 ¹H NMR (CDCl₃) δ 3.10 (3H, s), 3.74 (3H, s), 4.09 (2H, s), 6.72 (2H, d, J = 9.1 Hz), 6.96 (1H, d, J = 9.0 Hz), 7.03 (2H, d, J = 9.1 Hz), 8.43 (1H, dd, J = 9.0 Hz, 2.9 Hz), 9.06 (1H, d, J = 2.9 Hz). 159 —H —H —H —Ac —C₂H₅ 1 ¹H NMR (DMSO-d₆) δ 1.20 (3H, t, J = 7.1 Hz), 1.87 (3H, s), 4.12 (2H, q, J = 7.1 Hz), 4.37 (2H, s), 7.28- 7.35 (3H, m), 7.48 (2H, d, J = 8.7 Hz), 8.65 (1H, dd, J = 2.9 Hz, 9.1 Hz), 9.05 (1H, d, J = 2.9 Hz). 160 —H —H —H —CH₃ —CH₃ 2 ¹H NMR (CDCl₃) δ 2.59-2.64 (2H, m), 2.96 (3H, s), 3.67-3.72 (5H, m), 6.76 (2H, d, J = 9.1 Hz), 6.97 (1H, d, J = 9.1 Hz), 7.05 (2H, d, J = 8.9 Hz), 8.43 (1H, dd, J = 9.1 Hz, 3.0 Hz), 9.06 (1H, d, J = 2.8 Hz). 161 —F —H —F —H —C₂H₅ 1 ¹H NMR (CDCl₃) δ 1.32 (3H, t, J = 7.1 Hz), 3.91 (2H, d, J = 5.5 Hz), 4.28 (2H, q, J = 7.1 Hz), 4.57- 4.71 (1H, m), 6.43 (1H, dd, J = 7.9 Hz, 11.6 Hz), 6.94 (1H, dd, J = 7.0 Hz, 11.0 Hz), 7.08 (1H, d, J = 9.0 Hz), 8.49 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.01 (1H, d, J = 2.8 Hz). 162 —F —F —H —CH₃ —(CH₃)₃ 0 ¹H NMR (CDCl₃) δ 1.51 (9H, s), 3.30 (3H, s), 6.95-7.10 (2H, m), 7.21 (1H, d, J = 9.1 Hz), 8.54 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.00 (1H, d, J = 2.8 Hz). 163 —CH₃ —H —CH₃ —C₂H₅ —C₂H₅ 1 ¹H NMR (CDCl₃) δ 1.08 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 2.07 (3H, s), 2.28 (3H, s), 3.21 (2H, q, J = 7.1 Hz), 3.78 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 6.86 (1H, s), 6.95 (1H, d, J = 9.1 Hz), 7.07 (1H, s), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz). 164 —COOCH₃ —H —H —C₂H₅ —(CH₃)₃ 1 MS 431(M⁺) 165 —CH₃ —H —CH₃ —CH₃ —C₂H₅ 1 ¹H NMR (CDCl₃) δ 1.27 (3H, t, J = 7.1 Hz), 2.08 (3H, s), 2.28 (3H, s), 2.89 (3H, s), 3.73 (2H, s), 4.19 (2H, q, J = 7.1 Hz), 6.85 (1H, s), 6.96 (1H, d, J = 9.1 Hz), 7.01 (1H, s), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz). 166 —CN —H —H —CH₃ —(CH₃)₃ 1 MS 384(M⁺) 167 —H —H —CF₃ —C₂H₅ —C₂H₅ 1 MS 413(M⁺)

TABLE 23

Reference Example No. R₁₆₀ R₁₆₁ ¹H NMR (CDCl₃) δppm 168 —H

1.27 (3H, t, J = 7.0 Hz), 1.41-1.48 (2H, m), 1.85 (2H, brd, J = 13.0 Hz), 1.95 (1H, m), 2.29 (2H, d, J = 7.0 Hz), 2.76 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.65 (2H, brd, J = 12.0 Hz), 4.16 (2H, q, J = 7.0 Hz), 6.96- 6.99 (3H, m), 7.03 (2H, d, J = 9.0 Hz), 8.44 (1H, dd, J = 9.0 Hz, 3.0 Hz), 9.05 (1H, d, J = 3.0 Hz). 169 —H morpholino 3.18-3.19 (4H, m), 3.86-3.89 (4H, m), 6.94-7.01 (3H, m), 7.05-7.11 (2H, m), 8.45 (1H, dd, J = 9.2 Hz, 3.0 Hz), 9.05 (1H, d, J = 3.0 Hz). 170 —H

2.47-2.62 (4H, m), 2.96-3.14 (4H, m), 3.49 (2H, s), 7.11 (1H, d, J = 9.0 Hz), 7.19-7.37 (7H, m), 7.81 (2H, d, J = 8.7 Hz), 8.52 (1H, dd, J = 9.0 Hz, 2.0 Hz), 9.02 (1H. d, J = 2.0 Hz). 171 —H

1.28 (3H, t, J = 7.0 Hz), 1.90 (2H, dq, J = 4.0 Hz, 11.5 Hz), 2.04 (2H, brd, J = 13.0 Hz), 2.43 (1H, m), 2.82 (2H, dt, J = 3.0 Hz, 12.0 Hz), 3.63 (2H, dt, J = 13.0 Hz, 3.0 Hz), 4.17 (2H, q, J = 7.0 Hz), 6.97- 6.99 (3H, m), 7.04 (2H, d, J = 9.0 Hz), 8.44 (1H, dd, J = 9.0 Hz, 3.0 Hz), 9.05 (1H, d, J = 3.0 Hz). 172 —H

1.28 (3H, t, J = 7.0 Hz); 1.70 (2H, m), 1.84 (1H, m), 2.04 (1H, m), 2.69 (1H, m), 2.86 (1H, m), 3.08 (1H, dd, J = 12.0 Hz, 10.0 Hz), 3.46 (1H, brd, J = 12.0 Hz), 3.69 (1H, dd, J = 12.0 Hz, 4.0 Hz), 4,18 (2H, q, J = 7.0 Hz), 6.97-7.05 (5H, m), 8.45 (1H, dd, J = 9.0 Hz, 3.0 Hz), 9.06 (1H, d, J = 3.0 Hz). 173 —COOCH₃

2.61-2.64 (4H, m), 3.24-3.28 (4H, m), 3.58 (2H, s). 3.68 (3H, s), 7.03-7.16 (3H, m), 7.26-7.36 (5H, m), 7.54 (1H, d, J = 2.8 Hz), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.97 (1H, d, J = 2.8 Hz). 174 —H

2.43 (4H, t, J = 5.1 Hz), 3.40 (4H, t, J = 5.1 Hz), 3.43 (2H, s), 4.46 (2H, t, J = 5.5 Hz), 4.79 (1H, t, J = 5.5 Hz), 5.95 (2H, s), 6.74 (2H, s), 6.85 (1H, s), 7.05 (1H, d, J = 9.1 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.4 Hz), 8.48 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz). 175 —CH₃ —NHCOCOOC₂H₅ 1.33 (3H, t, J = 7.1 Hz), 2.07 (3H, s), 4.32 (2H, q, J = 7.1 Hz), 7.15 (1H, d, J = 8.7 Hz), 7.27 (1H, dd, J = 9.2 Hz, 0.5 Hz), 7.63 (1H, dd, J = 8.6 Hz, 2.5 Hz), 7.71 (1H, d, J = 2.5 Hz), 8.62 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01 (1H, dd, J = 2.8 Hz, 0.5 Hz), 10.82 (1H, brs).

TABLE 24

Reference Example No. R₁₆₂ R₁₆₃ ¹H NMR (solvent) δppm 176 —H —Ac (CDCl₃) 2.60 (3H, s), 7.10-9.00 (7H, m). 177 —H —CHO (CDCl₃) 7.14 (1H, d, J = 9.0 Hz), 7.35 (2H, d, J = 8.7 Hz), 8.00 (2H, d, J = 8.7 Hz), 8.54 (1H, dd, J = 9.0 Hz, 1.8 Hz), 9.04 (1H, d, J = 1.8 Hz), 10.03 (1H, s). 178 —H —C₂H₅ (CDCl₃) 1.28 (3H, t, J = 7.6 Hz), 2.70 (2H, q, J = 7.6 Hz), 7.01 (1H, dd, J = 9.1 Hz, 0.7 Hz), 7.07 (2H, d, J = 8.7 Hz), 7.28 (2H, d, J = 8.7 Hz), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, dd, J = 2.8 Hz, 0.7 Hz). 179 —CH₃ —CHO (CDCl₃) 2.25 (3H, s), 7.14 (1H, d, J = 8.9 Hz), 7.24 (1H, d, J = 8.2 Hz), 7.81 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.85 (1H, s), 8.53 (1H, dd, J = 8.9 Hz, 2.6 Hz), 9.00 (1H, d, J = 2.6 Hz), 10.00 (1H, s). 180 —H

(CDCl₃) 1.70-1.93 (4H, m), 2.45-2.56 (2H, m), 3.22-3.36 (2H, m), 4.62 (2H, s), 7.03 (1H, d, J = 9.2 Hz), 7.12 (2H d, J = 8.6 Hz), 7.35 (2H, d, J = 8.6 Hz), 8.47 (1H, dd, J = 9.2 Hz, 2.6 Hz), 9.04 (1H, d, J = 2.6 Hz). 181 —H

(CDCl₃) 2.46-2.47 (4H, m), 2.77-2.99 (2H, m), 3.46 (2H, s), 3.51-3.57 (4H, m), 3.64- 3.73 (1H, m), 3.90-3.96 (1H, m), 4.30- 4.36 (1H, m), 5.96 (2H, s), 6.75-6.86 (3H, m), 7.04 (1H, d, J = 9.1 Hz), 7.17 (2H, d, J = 9.1 Hz), 7.70 (2H, d, J = 8.9 Hz), 8.48 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.03 (1H, d, J = 2.8 Hz). 182 —H

(CDCl₃) 1.51 (9H, s), 3.80 (4H, m), 4.27 (2H, s), 7.07 (1H, d, J = 9.1 Hz), 7.21 (2H, dd, J = 6.8 Hz, 2.1 Hz), 7.38 (2H, dd, J = 6.8 Hz, 2.1 Hz), 8.49 (1H, dd, J = 9.1 Hz, 2.8 Hz). 9.04 (1H, d, J = 2.8 Hz). 183 —H

(CDCl₃) 3.35-3.55 (4H, m), 3.96 (2H, s), 4.58 (2H, s), 5.96 (2H, s), 6.73-6.78 (2H, m), 6.81 (1H, s), 6.91 (2H, d, J = 9.1 Hz), 7.00 (1H, d, J = 9.1 Hz), 7.09 (2H, d, J = 9.1 Hz), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz). 184 —H —NHCONHPh (DMSO-d₆) 6.96 (1H, t, J = 6.5 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.21 (1H, d, J = 9.1 Hz), 7.27 (2H, t, J = 8.3 Hz), 7.45 (2H, d, J = 8.3 Hz), 7.52 (2H, d, J = 8.8 Hz), 8.60 (1H, dd, J = 2.8 Hz, 9.1 Hz), 8.70 (1H, s), 8.77 (1H, s), 9.02 (1H, d, J = 2.8 Hz).

TABLE 25

Reference Example No. R₁₆₄ R₁₆₅ R₁₆₆ M mp (° C.) or ¹H NMR (solvent) δppm 185 —NO₂ —CH₃ piperonyl 2 mp 142.0-143.0 186 —NO₂ —H benzyl 1 ¹H NMR (DMSO-d₆) 3.36 (2H, t, J = 8.1 Hz), 3.84 (2H, t, J = 8.1 Hz), 4.40 (2H, s), 7.15- 7.25 (3H, m), 7.26-7.34 (3H, m), 7.35- 7.41 (2H, m), 7.61-7.71 (2H, m), 8.59 (1H, dd, J = 2.9 Hz, 9.1 Hz), 9.02 (1H, d, J = 9.1 Hz). 187 —NO₂ —CH₃ piperonyl 1 ¹H NMR (DMSO-d₆) 2.05 (3H, s), 3.29- 3.41 (2H, m), 3.71-3.88 (2H, m), 4.29 (2H, s), 5.60 (2H, s), 6.74-6.81 (1H, m), 6.82-6.92 (2H, m), 7.09 (1H, d, J = 8.8 Hz), 7.21 (1H, d, J = 9.1 Hz), 7.49 (1H, d, J = 2.6 Hz, 8.8 Hz), 7.51-7.57 (1H, m), 8.60 (1H, d, J = 9.1 Hz), 9.00 (1H, d. J = 2.9 Hz). 188 —NO₂ —CH₃ 3,4- (CH₃O)₂PhCH₂— 2 ¹H NMR (CDCl₃) 2.00-2.15 (2H, m), 2.14 (3H, s), 3.31 (2H, t, J = 6.0 Hz), 3.73 (2H, d, J = 6.0 Hz), 3.88 (3H, s), 3.89 (3H, s), 4.57 (2H, s), 6.83 (1H, d, J = 8.1 Hz), 6.87 (1H, dd, J = 1.9 Hz, 8.1 Hz), 6.91 (1H, d, J = 1.9 Hz), 698-7.06 (2H, m), 7.20 (1H, dd, J = 2.4 Hz, 8.6 Hz), 7.29 (1H, d, J = 2.4 Hz), 8.46 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.04 (1H, d, J = 2.8 Hz). 189 —NO₂ —CH₃ —CH₂COOC(CH₃)₃ 2 ¹H NMR (CDCl₃) 1.48 (9H, s), 2.12 (3H, s), 2.12-2.24 (2H, m), 3.48 (2H, t, J = 5.9 Hz), 3.77 (2H, t, J = 5.9 Hz), 4.05 (2H, s), 6.92- 7.06 (2H, m), 7.17 (1H, dd, J = 2.6 Hz, 8.6 Hz), 8.45 (1H, dd, J = 2.9 Hz, 9.1 Hz), 9.04 (1H, d, J = 2.9 Hz). 190 —Br —CH₃ piperonyl 2 ¹H NMR (CDCl₃) 1.94-2.18 (2H, m), 2.15 (3H, s), 3.30 (2H, d, J = 6.0 Hz), 3.71 (2H, d, J = 6.0 Hz), 4.52 (2H, s), 5.95 (2H, s), 6.69-6.82 (3H, m), 6.88 (1H, s), 7.00 (1H, d, J = 8.6 Hz), 7.15 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.24 (1H, d, J = 2.6 Hz), 7.73 (1H, dd, J = 2.5 Hz, 8.6 Hz), 8.20 (1H, d, J = 2.5 Hz). 191 —Br —CH₃ 3,4- (CH₃O)₂PhCH₂— 2 ¹H NMR (CDCl₃) 1.95-2.11 (2H, m), 2.14 (3H, s), 3.30 (2H, t, J = 5.9 Hz), 3.70 (2H, t, J = 5.9 Hz), 3.88 (3H, s), 3.88 (3H, s), 4.56 (2H, s), 6.74-6.92 (4H, s), 7.00 (1H, d, J = 8.5 Hz), 7.15 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.24 (1H, d, J = 2.4 Hz), 7.73 (1H, dd, J = 2.6 Hz, 8.8 Hz), 8.19 (1H, dd, J = 0.5 Hz, 2.6 Hz).

TABLE 26

Reference Example No. R₁₆₇ ¹H NMR (CDCl₃) δppm or MS 192

¹H NMR 1.24 (3H, t, J = 7.1 Hz), 3.07 (3H, s), 4.05 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 6.44-6.45 (1H, m), 6.49-6.53 (1H, m), 6.57-6.61 (1H, m), 6.97 (1H, d, J = 9.1 Hz), 7.25-7.31 (1H, m), 8.44 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.07 (1H, d, J = 2.8 Hz). 193

¹H NMR 3.93 (3H, s), 7.08-7.11 (1H, m), 7.26-7.40 (1H, m), 7.51-7.57 (1H, m), 7.83-7.84 (1H, m), 7.96-8.00 (1H, m), 8.49-8.53 (1H, m), 9.02-9.03 (1H, m). 194

MS 488(M⁺) 195

¹H NMR 4.00 (3H, s), 7.14 (1H, d, J = 8.9 Hz), 7.37 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.67 (1H, d, J = 2.3 Hz), 7.87 (1H. d, J = 8.6 Hz), 8.04 (1H, d, J = 8.9 Hz), 8.11 (1H, dd, J = 8.6 Hz, 1.7 Hz), 8.51- 8.55 (1H, m), 8.64 (1H, brs), 9.05 (1H, d, J = 2.8 Hz). 196

¹H NMR 4.03 (3H, s), 7.20 (1H, d, J = 9.1 Hz), 7.31 (1H, d, J = 8.1 Hz), 7.51- 7.57 (1H, m), 7.65-7.71 (1H, m), 7.94 (1H, d, J = 8.4 Hz), 8.29 (1H, d, J = 8.1 Hz), 8.55 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.99 (1H, d, J = 2.8 Hz), 9.05 (1H, d, J = 8.7 Hz). 197

¹H NMR 1.47 (3H, t, J = 7.1 Hz), 4.49 (2H, t, J = 7.1 Hz), 7.11 (1H, d, J = 8.9 Hz), 7.42 (1H, dd, J = 9.4 Hz, 2.5 Hz), 7.52-7.58 (1H, m), 7.67 (1H, d, J = 2.5 Hz), 7.99 (1H, d, J = 8.2 Hz), 8.21 (1H, dd, J = 7.3 Hz, 1.2 Hz), 8.51 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04-9.08 (2H, m). 198

¹H NMR (CDCl₃) 2.11 (3H, s), 2.19 (2H, t, J = 5.9 Hz), 2.34-2.50 (4H, m), 3.42 (2H, s), 3.40-3.47 (2H, m), 3.51(2H, t, J = 5.9 Hz), 3.56-3.76 (2H, m), 3.78 (2H, t, J = 5.7 Hz), 4.20 (2H, s), 5.94 (2H, s), 6.69-6.77 (2H, m), 6.84 (1H, d, J = 1.0 Hz), 6.96-7.02 (2H, m), 7.17 (1H, dd, J = 2.6 Hz, 8.5 Hz), 7.24- 7.28 (1H, m), 8.45 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.04 (1H, d, J = 2.8 Hz).

TABLE 27

Reference Example No. R₁₆₈ R₁₆₉ M ¹H NMR (solvent) δppm 199 —H benzyl 2 (CDCl₃) 2.36-2.45 (4H, m), 2.63-2.68 (2H, m), 2.99- 3.05 (2H, m), 3.41-3.45 (2H, m), 3.52 (2H, s), 3.64- 3.67 (2H, m), 7.01-7.11 (3H, m), 7.29-7.34 (7H, m), 8.47 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8 Hz). 200 —H piperonyl 2 (CDCl₃) 2.33-2.41 (4H, m), 2.62-2.67 (2H, m), 2.98- 3.04 (2H, m), 3.39-3.43 (4H, m), 3.62-3.65 (2H, m), 5.94 (2H, s), 6.73-6.77 (2H, m), 6.84 (1H, s), 7.00- 7.10 (3H, m), 7.26-7.31 (2H, m), 8.44-8.48 (1H, m), 9.03 (1H, dd, J = 3.0 Hz, 0.5 Hz). 201 —F benzyl 0 (CDCl₃) 2.49 (4H, brs), 3.49-3.56 (4H, m), 3.79 (2H, brs), 7.15 (1H, d, J = 8.9 Hz), 7.24-7.38 (3H, m), 8.53 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.99 (1H, d, J = 2.8 Hz). 202 —H benzyl 0 (DMSO-d₆) 2.41 (4H, brs), 3.33 (2H, brs), 3.52 (4H, brs), 7.24-7.27 (8H, m), 7.50 (2H, d, J = 7.9 Hz), 8.64 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz). 203 —H 4-CH₃OPhCH₂— 0 (CDCl₃) 2.46 (4H, brs), 3.44-3.90 (4H, m), 3.49 (2H, s), 3.81 (3H. s), 6.85-6.89 (2H, m), 7.06 (1H, d. J = 8.9 Hz), 7.18-7.27 (4H, m), 7.48-7.53 (2H, m), 8.48- 8.52 (1H, m), 9.03 (1H, d, J = 2.8 Hz). 204 —H piperonyl 0 (CDCl₃) 2.46 (4H, brs), 3.46 (2H, s), 3.52 (2H, brs), 3.77 (2H, brs), 5.95 (2H, s), 6.75 (2H, s), 6.86 (1H, s), 7.07 (1H, dd, J = 9.1 Hz, 0.5 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.51 (2H, d, J = 8.6 Hz), 8.50 (1H, dd, J = 8.9 Hz, 2.8 Hz), 9.03 (1H, dd, J = 2.8 Hz, 0.5 Hz). 205 —H 3-pyridyl 0 (CDCl₃) 3.27 (4H, brs), 3.84 (4H, brs), 7.08-7.12 (1H, m), 7.21-7.27 (4H, m), 7.54-7.59 (2H, m), 8.16- 8.18 (1H, m), 8.34 (1H, brs), 8.52 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, dd, J = 2.8 Hz, 0.5 Hz).

TABLE 28

Reference Example No. Xa₅ R₁₇₀ M ¹H NMR (CDC1₃) δppm 206 —O— piperonyl 1 2.43 (4H, brs), 3.42 (2H, s), 3.58 (2H, t, J = 5.0 Hz), 3.64 (2H, t, J = 5.0 Hz), 4.70 (2H, s), 5.95 (2H, s), 6.70-6.79 (2H, m), 6.84 (1H, d, J = 0.6 Hz), 7.01 (3H, d, J = 9.1 Hz), 7.09 (2H, d, J = 9.1 Hz), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz). 207 —CH(OH)— benzyl 0 1.90-2.05 (1H, m), 2.21-2.68 (3H, m), 3.11- 3.25 (1H, m), 3.28-3.40 (1H, m), 3.45 (2H, s), 3.73 (2H, t, J = 5.1 Hz), 4.77 (1H, d, J = 6.3 Hz), 5.24 (1H, d, J = 6.3 Hz), 7.04 (1H, d, J = 8.9 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.21-7.35 (5H, m), 7.38 (2H, d, J = 8.7 Hz), 8.48 (1H, dd, J = 8.9 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz). 208

piperonyl 1 0.65-0.70 (2H, m), 0.81-0.88 (2H, m), 2.41- 2.48 (4H, m), 2.77-2.85 (1H, m), 3.45 (2H, s), 3.49-3.52 (2H, m), 3.60-3.63 (2H, m), 4.20 (2H, s), 5.95 (2H, s), 6.71-6.78 (2H, m), 6.86 (1H, brs), 6.90-7.02 (5H, m), 8.39-8.44 (1H, m), 9.06 (1H, d, J = 2.8 Hz). 209 —O— benzyl 1 2.45 (4H, t, J = 4.5 Hz), 3.52 (2H, s), 3.59 (2H, t, J = 4.9 Hz), 3.65 (2H, t, J = 4.9 Hz), 4.70 (2H, s), 7.00 (2H, d, J = 9.2 Hz), 7.01 (1H, d, J = 9.0 Hz), 7.08 (2H, d, J = 9.2 Hz), 7.21-7.40 (5H, m), 8.46 (1H, dd, J = 9.0 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz). 210 —N(CH₃)— benzyl 0 2.32 (4H, brs), 3.24 (3H, s), 3.28 (4H, brs), 3.48 (2H, brs), 7.04 (1H, d, J = 9.1 Hz), 7.11 (2H, d, J = 9.0 Hz), 7.15 (2H, d, J = 9.0 Hz), 7.22- 7.40 (5H, m), 8.48 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).

TABLE 29

Reference Example ¹H NMR (CDCl₃) No. R₁₇₁ R₁₇₂ Xa₆ R₁₇₃ R₁₇₄ R₁₇₅ δppm or MS 211 —NO₂ —H —N(CH₃)— —CH₃ —H —C₂H₅ ¹H NMR 1.25 (3H, t, J = 7.1 Hz), 1.50 (3H, d, J = 7.1 Hz), 2.93 (3H, s), 4.18 (2H, q, J = 7.1 Hz), 4.48 (1H, q, J = 7.3 Hz), 6.82 (2H, d, J = 9.2 Hz), 6.97 (1H, d, J = 9.1 Hz), 7.03 (2H, d, J = 9.0 Hz), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz). 212 —NO₂ —H —N(CH₃)— —CH₃ —CH₃ —C₂H₅ ¹H NMR 1.24 (3H, t, J = 7.1 Hz), 1.46 (6H, s), 2.94 (3H, s), 4.18 (2H. q, J = 7.1 Hz), 6.97 (1H, dd, J = 9.1 Hz, 0.5 Hz), 7.00- 7.08 (4H, m), 8.45 (1H, dd, J = 9.1 Hz, 3.0 Hz). 9.05 (1H, dd, J = 2.8 Hz, 0.5 Hz). 213 —NO₂ —CH₃ —N(CH₃)— —CH₃ —H —C₂H₅ ¹H NMR 1.26 (3H, t, J = 7.1 Hz), 1.49 (3H, d, J = 7.3 Hz), 2.10 (3H, s), 2.91 (3H, s), 4.13- 4.24 (2H, m), 4.48 (1H, q, J = 7.3 Hz), 6.64- 6.68 (2H, m), 6.91- 6.96 (2H, m), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, dd, J = 2.8 Hz, 0.5 Hz), 214 —NO₂ —H none —CH₃ —CH₃ —CH₃ MS 316(M⁺) 215 —Br —OCH₃ —CH₂— —H —H —C₂H₅ ¹H NMR 1.26 (3H, t, J = 7.1 Hz), 2.63-2.68 (2H, m), 2.94- 3.00 (2H, m), 3.75 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 6.80-6.86 (3H, m), 7.03 (1H, d, J = 7.9 Hz), 7.73 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.16 (1H, dd, J = 2.6 Hz, 0.7 Hz). 216 3,4-Cl₂PhCH₂NHCO— —H —CH₂— —H —H —C₂H₅ MS 472(M⁺) 217 4-CF₃PhCH₂NHCO— —H —CH₂— —H —H —C₂H₅ MS 472(M⁺)

TABLE 30

Reference Example No. R₁₇₆ R₁₇₇ ¹H NMR (CDCl3) δppm or MS 218 4-CF₃PhCO—

¹H NMR 1.26 (3H, t, J = 7.1 Hz), 2.64-2.69 (2H, m), 2.95-3.01 (2H, m), 3.76 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 6.83-6.89 (2H, m), 7.03- 7.10 (2H, m), 7.73-7.76 (2H, m), 7.86-7.89 (2H, m), 8.21 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.55(1H, dd, J = 2.5 Hz, 0.7 Hz). 219 3,4-Cl₂PhNHCO—

¹H NMR 1.20 (3H, t, J = 7.1 Hz), 3.44 (2H, q, J = 7.1 Hz), 3.56 (3H, s), 4.04 (2H, s), 5.17 (2H, s), 6.15- 6.18 (2H, m), 6.83 (1H, d, J = 8.7 Hz), 6.88 (1H, d, J = 8.9 Hz), 7.29-7.35 (6H, m), 7.44 (1H, dd, J = 8.7 Hz, 2.5 Hz), 7.82 (1H, d, J = 2.3 Hz), 3.10 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.59 (1H, d, J = 2.5 Hz), 8.72 (1H, brs). 220 3,4-Cl₂PhNHCO—

MS 501(M⁺) 221 4-CF₃PhNHCO—

MS 501(M⁺) 222 —COOC₂H₅ 4-NO₂Ph— ¹H NMR 1.40 (3H, t, J = 7.1 Hz), 4.40 (2H, q, J = 7.1 Hz), 7.08 (1H, d, J = 8.6 Hz), 7.32 (2H, d, J = 9.0 Hz), 8.31 (2H, d, J = 9.0 Hz), 8.37 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.82 (1H, d, J = 2.3 Hz). 223 4-CF₃PhNHCO— 4-CHOPh— MS 386(M⁺) 224 —COOC₂H₅

¹H NMR 1.39 (3H, t, J = 7.1 Hz), 2.28 (3H, s), 4.39 (2H, q, J = 7.1 Hz), 7.07 (1H, dd, J = 8.6 Hz, 0.5 Hz), 7.21 (1H, d, J = 8.9 Hz), 8.13 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.20 (1H, d, J = 2.8 Hz), 8.36 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.78 (1H, dd, J = 2.8 Hz, 0.6 Hz). (CHOPh means a formylphenyl group. Hereinafter CHOPh indicates the same meaning.)

TABLE 31

Reference Example mp (° C.) or ¹H NMR No. R₁₇₈ R₁₇₉ R₁₈₀ Form (solvent) δppm 225 4-CF₃PhNHCO— —CH₃ —NHCOCOOC₂H₅ free ¹H NMR (DMSO-d₆) 1.33 (3H, t, J = 7.1 Hz), 2.08 (3H, s), 4.33 (2H, q, J = 7.1 Hz), 7.12 (1H, d, J = 8.7 Hz), 7.17 (1H, d, J = 8.6 Hz), 7.63 (1H, dd, J = 8.7 Hz, 2.5 Hz), 7.72- 7.75 (3H, m), 7.98 (2H, d, J = 8.7 Hz), 8.37 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.69 (1H, d, J = 2.5 Hz), 10.62 (1H, brs), 10.81 (1H, brs). 226 3,4-Cl₂PhNHCO— —CH₃

hydro- bromide mp 132.0-134.0 227 —NO₂ —CH₃

free ¹H NMR (CDCl₃) 1.28 (3H, t, J = 7.1 Hz), 1.86-1.95 (2H, m), 2.02- 2.06 (2H, m), 2.10 (3H, s), 2.40-2.48 (1H, m), 2.76- 2.85 (2H, m), 3.61- 3.65 (2H, m), 4.17 (2H, q, J = 7.1 Hz), 6.79-6.97 (4H, m), 8.43 (1H, dd, J = 9.1 Hz, 3.0 Hz), 9.04 (1H, d, J = 2.8 Hz). 228 —NO₂ —OCH₃

free ¹H NMR (CDCl₃) 1.28 (3H, t, J = 7.1 Hz), 1.41-1.50 (2H, m), 1.84- 2.04 (3H, m), 2.30 (2H, d, J = 6.9 Hz), 2.78 (2H, dd, J = 12.0 Hz, 9.7 Hz), 3.65 (2H, d, J = 12.4 Hz), 3.73 (3H, s), 4.16 (2H, q, J = 7.3 Hz), 6.53 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.59 (1H, d, J = 2.6 Hz), 6.96- 7.02 (2H, m), 8.42 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz). 229 —NO₂ —CH₃

free ¹H NMR (CDCl₃) 1.27 (3H, t, J = 7.1 Hz), 1.37-1.49 (2H, m), 1.83- 2.03 (3H, m), 2.10 (3H, s), 2.29 (2H, d, J = 6.9 Hz), 2.74 (2H, dd, J = 12.2 Hz, 10.1 Hz), 3.64 (2H, d, J = 12.4 Hz), 4.15 (2H, q, J = 7.3 Hz), 6.77-6.83 (2H, m), 6.91-6.97 (2H, m), 8.42 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02 (1H, d. J = 2.8 Hz).

TABLE 32

Reference Example ¹H NMR (CDCl₃) No. R₁₈₁ R₁₈₂ R₁₈₃ R₁₈₄ R₁₈₅ δppm or MS 230 —Br —CH₃ —H —H

¹H NMR 2.09 (3H, s), 2.41-2.45 (4H, m), 3.01 (3H, s), 3.43 (2H, s), 3.49 (2H, brs), 3.63 (2H, brs), 4.07 (2H, brs), 5.93 (2H, s), 6.51-6.56 (2H, m), 6.68-6.77 (3H, m), 6.85-6.91 (2H, m), 7.68 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.19 (1H, d, J = 2.5 Hz). 231 3,4-Cl₂PhNHCO— —H —CF₃ —H —N(CH₃)CH₂COOC₂H₅ MS 541(M⁺) 232 4-CF₃PhNHCO— —H —CF₃ —H —N(CH₃)CH₂COOC₂H₅ MS 541(M⁺) 233 3,4- Cl₂PhCH₂NHCO— —H —CF₃ —H —N(CH₃)CH₂COOC₂H₅ MS 555(M⁺) 234 4-CF₃CH₂NHCO— —H —CF₃ —H —N(CH₃)CH₂COOC₂H₅ MS 555(M⁺) 235 —Br —F —H —F —N(CH₃)CH₂COOC₂H₅ ¹H NMR 1.26 (3H, t, J = 7.1 Hz), 2.99 (3H, s), 4.03 (2H, s), 4.18 (2H, q J = 7.1 Hz), 6.76 (1H, d, J = 8.2 Hz, 12.1 Hz), 6.84- 6.95 (2H, m), 7.77 (1H, dd, J = 2.6 Hz, 8.7 Hz), 8.17 (1H, d, J = 2.6 Hz).

TABLE 33

Reference Example No. R₁₈₆ Xa₇ R₁₈₇ M ¹H NMR (solvent) δppm 236 —COOC₂H₅ —CH₂— piperonyl 1 (DMSO-d₆) 1.31 (3H, t, J = 7.0 Hz), 2.28 (1H, brs), 2.60-2.66 (2H, m), 2.80- 2.86 (2H, m), 3.38 (2H, s), 3.40- 3.46 (4H, m), 4.31 (2H, q, J = 7.0 Hz), 5.98 (2H, s), 6.72-6.76 (1H, m), 6.84 (2H, d, J = 8.4 Hz), 7.06-7.11 (3H, m), 7.30 (2H, d, J = 8.4 Hz), 8.30 (1H, dd, J = 8.6 Hz, 2.4 Hz), 8.68 (1H, d, J = 2.4 Hz). 237 —COOC₂H₅ none benzyl 0 (CDCl₃) 1.39 (3H, t, J = 7.3 Hz), 2.48 (4H, brs), 3.55-3.91 (6H, m), 4.38 (2H, q, J = 7.3 Hz), 6.97 (1H, d, J = 8.6 Hz), 7.17-7.19 (2H, m), 7.20- 7.34 (5H, m), 7.46-7.49 (2H, m), 8.31 (1H, dd, J = 8.6 Hz, 2.4 Hz), 8.82 (1H,d, J = 2.4 Hz). 238 —Br —N(CH₃)— piperonyl 1 (CDCl₃) 2.41-2.45 (4H, m), 3.03 (3H, s), 3.43 (2H, s), 3.47-3.51 (2H, m), 3.61- 3.65 (2H, m), 4.09 (2H, s), 5.95 (2H, s), 6.68-6.85 (6H, m), 6.96-7.02 (2H, m), 7.70 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.20 (1H, d, J = 2.5 Hz). 239 —Br —CH₂— piperonyl 1 (CDCl₃) 2.31-2.41 (4H, m), 2.59- 2.65 (2H, m), 2.95-3.00 (2H, m), 3.38- 3.42 (4H, m), 3.61-3.65 (2H, m), 5.95 (2H, s), 6.70-6.77 (2H, m), 6.81- 6.84 (2H, m), 7.01-7.06 (2H, m), 7.22- 7.27 (2H, m), 7.76 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.20-8.21 (1H, m). 240 —Br none benzyl 0 (CDCl₃) 2.47 (4H, brs), 3.49-3.55 (6H, m), 6.86 (1H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.28-7.33 (5H, m), 7.45 (2H, d. J = 8.6 Hz), 7.80 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.22 (1H, d, J = 2.5 Hz). 241 —COOCH₃ —N(CH₃)— piperonyl 1 (CDCl₃) 2.41-2.45 (4H, m), 3.04 (3H, s), 3.43 (2H, s), 3.47-3.49 (2H, m), 3.63 (2H, s), 3.91 (3H, s), 4.10 (2H, s), 5.95 (2H, s), 6.69-6.75 (4H, m), 6.84 (1H, dd, J = 8.7 Hz, 0.7 Hz), 6.85 (1H, brs), 7.02 (2H, d, J = 9.2 Hz), 8.21 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.82 (1H, dd, J = 2.5 Hz, 0.7 Hz). 242 —COOC₂H₅ none piperonyl 0 (CDCl₃) 1.39 (3H, t, J = 7.1 Hz), 2.45 (4H, brs), 3.45 (2H, s), 3.54- 3.75 (4H, m), 4.38 (2H, q, J = 7.1 Hz), 5.95 (2H, s), 6.71-6.75 (2H, m), 6.86 (1H, s), 6.97 (1H, d, J = 8.6 Hz), 7.19 (2H, d, J = 8.6 Hz), 7.48 (2H, d, J = 8.7 Hz), 8.30 (1H, dd, J = 2.3 Hz, 8.6 Hz), 8.82 (1H, d, J = 2.3 Hz).

TABLE 34 Reference Example No. Chemical Structure MS (M⁺) 243

413 244

504 245

413 246

574

Reference Example 247 Production of 4-(5-nitropyridin-2-yloxy)phenylamine

To a solution of sodium hydroxide (730 mg, 18.25 mmol) in methanol was added 4-aminophenol (2.00 g, 18.32 mmol). After the resulting mixture was made to dissolve, methanol was evaporated under reduced pressure. To the residue was added DMF (20 mL), and then 2-chloro-5-nitropyridine (2.91 g, 18.35 mmol). The reaction solution was stirred for 1.5 hours at 70° C., and then concentrated under reduced pressure. Water was added to the residue, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, after which solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 3.37 g of the title compound.

Appearance: Black-red powder

¹H NMR (DMSO-d₆) δ 5.10 (2H, s), 6.61 (2H, d, J=8.9 Hz), 6.85 (2H, d, J=8.9 Hz), 7.08 (1H, d, J=9.0 Hz), 8.55 (1H, dd, J=9.0 Hz, 3.0 Hz), 9.01 (1H, d, J=3.0 Hz).

The following compounds were produced in the same manner as in Reference Example 247.

TABLE 35 Reference Example No. Chemical Structure ¹H NMR (solvent) δppm 248

(DMSO-d₆) 4.03 (2H, s), 6.96 (1H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.9 Hz), 7.17 (2H, d, J = 8.9 Hz), 7.48 (2H, d, J = 8.1 Hz), 7.66 (2H, d, J = 8.1 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.5 Hz), 8.08 (1H, d, J = 2.5 Hz), 9.12 (2H, brs). 249

(CDCl₃) 1.47 (9H, s), 2.94 (2H, d, J = 5.1 Hz), 3.10-3.80 (9H, m), 4.62 (1H, d, J = 5.1 Hz), 7.03 (1H, d, J = 9.1 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.31 (2H, d, J = 8.5 Hz), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01 (1H, d, J = 2.8 Hz).

TABLE 36

Reference Example No R₁₈₈ ¹H NMR (solvent) δppm 250 —CH₂OH (CDCl₃) 4.74 (2H, s), 7.04 (1H, d, J = 8.9 Hz). 7.13-7.18 (2H, m), 7.46 (2H, d, J = 8.3 Hz), 8.48 (1H, dd, J = 8.9 Hz, 2.6 Hz), 9.03 (1H, d, J = 2.6 Hz). 251 —(CH₂)₂OH (CDCl₃) 2.91 (2H, t, J = 6.6 Hz), 3.91 (2H, t, J = 6.6 Hz), 7.03 (1H, d, J = 9.2 Hz), 7.09-7.13 (2H, m), 7.32 (2H, d, J = 8.6 Hz), 8.47 (1H, dd, J = 9.2 Hz, 3.0 Hz), 9.04 (1H, d, J = 3.0 Hz). 252 —(CH₂)₂COOH (CDCl₃) 2.73 (2H, t, J = 7.9 Hz), 3.01 (2H, t, J = 7.9 Hz), 7.03 (1H, d, J = 8.9 Hz), 7.09 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 8.47 (1H, dd, J = 9.2 Hz, 3.0 Hz), 9.04 (1H, d, J = 2.6 Hz). 253 —(CH₂)₃COOH (DMSO-d₆) 2.01 (2H, dq, J = 15.0 Hz, 7.2 Hz), 2.46 (2H, t, J = 7.2 Hz), 2.72 (2H, t, J = 7.2 Hz), 7.02 (1H, d, J = 8.6 Hz), 7.08 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 8.46 (1H, dd, J = 8.6 Hz, 3.0 Hz), 9.04 (1H, d, J = 3.0 Hz).

Reference Example 254 Production of ethyl 3-[4-(3-nitrophenoxy)phenyl]-propionate

Under argon, to a solution of 3-iodonitrobenzene (3.00 g, 12.0 mmol) in pyridine (15 mL) were added ethyl 3-(4-hydroxyphenyl)propionate (2.81 g, 14.5 mmol), copper oxide (3.3.5 g, 42.2 mmol), and potassium carbonate (4.16 g, 30.1 mmol), and the resulting solution was heated to reflux for 40 hours. The reaction solution was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, and once insoluble matter had been filtered off, and the filtrate was extracted with ethyl acetate out. The ethyl acetate layer was washed with 1 M hydrochloric acid, water and a saturated sodium bicarbonate solution, and then washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1→6:1), to thereby yield 1.12 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7.1 Hz), 2.62 (2H, t, J=7.7 Hz), 2.95 (2H, t, J=7.7 Hz), 4.12 (2H, q, J=7.1 Hz), 6.96 (2H, d, J=8.6 Hz), 7.22 (2H, d, J=8.6 Hz), 7.29 (1H, dd, J=8.2 Hz, 2.3 Hz), 7.43 (1H, t, J=8.2 Hz), 7.74 (1H, s), 7.90 (1H, dd, J=8.2 Hz, 2.3 Hz).

Reference Example 255 Production of 1-(t-butoxycarbonyl) 4-[4-(4-nitrophenoxy)phenyl]piperazine

Potassium carbonate (15.7 g, 114 mmol) was added to a solution of 2-chloro-5-nitropyridine (4.50 g, 28.4 mmol) and 1-(4-hydroxyphenyl)piperazine dihydrochloride (7.13 g, 28.4 mmol) in DMF (80 mL). The resulting solution was stirred at room temperature for 8 hours. To this reaction solution was added di-t-butyl dicarbonate (6.81 g, 31.2 mmol), and stirred at room temperature for 2.5 days. To the reaction solution was charged with ethyl acetate, washed with water, and dried with anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3), to thereby yield 7.05 q of the title compound.

Appearance: Yellow needles

¹H NMR (CDCl₃) δ 1.49 (9H, s), 3.15 (4H, t, J=5.0 Hz), 3.59 (4H, t, J=5.0 Hz), 6.98 (2H, d, J=9.0 Hz), 7.00 (1H, d, J=9.0 Hz), 7.07 (2H, d, J=9.0 Hz), 8.45 (1H, dd, J=9.0 Hz, 2.5 Hz), 9.05 (1H, d, J=2.5 Hz).

Reference Example 256 Production of (ethyl{3-methoxy-4-[5-(4-trifluoromethylphenylcarbamoyl)pyridin-2-yloxy]phenyl}amino)acetate

Benzyl [ethyl (4-hydroxy-3-methoxyphenyl)amino]acetate (9.46 g, 30 mmol) and 6-chloro-N-(4-trifluoromethylphenyl)nicotinamide (9.02 g, 30 mmol) were dissolved in DMF (100 mL). To the resulting solution was added potassium carbonate (6.22 g, 45 mmol), and then stirred for 12 hours at 120° C. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and extracted with water. The pH of the aqueous layer was adjusted from 3 to 4 with 1 M hydrochloric acid, after which the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and evaporated to thereby yield 4.2 g of the title compound.

Appearance: crown powder

¹H NMR (DMSO-d₆) δ 1.19 (3H, t, J=7.1 Hz), 3.40 (2H, q, J=7.1 Hz), 3.63 (3H, s), 4.01 (2H, s), 6.17 (1H, d, J=8.9 Hz), 6.22 (1H, brs), 6.25 (1H, d, J=2.5 Hz), 6.87-6.90 (2H, m), 7.53 (2H, d, J=8.6 Hz), 7.76 (2H, d, J=8.4 Hz), 8.18 (1H, dd, J=8.7 Hz, 2.3 Hz), 8.67 (1H, d, J=2.1 Hz), 8.88 (1H, brs).

Reference Example 257 Production of ethyl methyl [2,5-difluoro-4-(5-nitropyridin-2-yloxy)phenyl]aminoacetate

To a solution of ethyl (2,5-difluoro-4-hydroxyphenyl)aminoacetate (1.1 g, 4.8 mmol) in DMF (25 mL) were added sodium bicarbonate (0.44 g, 5.2 mmol) and methyl iodide (1.69 mL, 28.6 mmol), and the resulting reaction solution was stirred for 2 days at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. Once the ethyl acetate layer had been washed with water, the ethyl acetate layer was dried with anhydrous magnesium sulfate, and evaporated. The residue was dissolved in DMF (30 mL), and to this resulting solution were added potassium carbonate (0.72 g, 5.2 mmol) and 2-chloro-5-nitropyridine (0.79 g, 5.0 mmol). The reaction solution was stirred for 2.5 days at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=8:1), to thereby yield 1.41 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.1 Hz), 3.01 (3H, s), 4.05 (2H, s), 4.19 (2H, q, J=7.1 Hz), 6.77 (1H, dd, J=8.2 Hz, 12.2 Hz), 6.92 (1H, dd, J=7.2 Hz, 12.8 Hz), 8.49 (1H, dd, J=2.8 Hz, 9.0 Hz), 9.02 (1H, d, J=2.8 Hz).

The following compounds were produced in the same manner as in Reference Example 257.

TABLE 37

Reference Example No. R₁₈₉ R₁₉₀ R₁₉₁ ¹H NMR (CDCl₃) δppm 258 —NO₂ —CH₃ —CH₃ 1.27(3H, t, J = 7.1 Hz), 2.05(3H, s), 2.29(3H, s), 2.87(3H, s), 3.71(2H, s), 4.18(2H, q, J = 7.1 Hz), 6.87(1H, d, J = 8.7 Hz), 6.97(1H, dd, J = 9.1 Hz, 0.3 Hz), 7.08(1H, d, J = 8.7 Hz), 8.45(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04(1H, dd, J = 2.8 Hz, 0.3 Hz). 259 4-CF₃PhCO— —H —C₂H₅ 1.23(3H, t, J = 7.1 Hz), 1.28(3H, t, J = 7.1 Hz), 2.12(3H, s), 3.46(2H, q, J = 7.1 Hz), 4.01 (2H, s), 4.21(2H, q, J = 7.1 Hz), 6.49-6.53(2H, m), 6.92- 6.96(2H, m), 7.73-7.77(2H, m), 7.86-7.89(2H, m), 8.17(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.59(1H, dd, J = 2.5 Hz, 0.7 Hz).

Reference Example 260 Production of ethyl 4-(3-[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]-2-oxotetrahydropyrimidin-1-yl)benzoate

Under a nitrogen atmosphere, to a solution of ethyl 4-[3-(4-benzyloxy-3-methyl)phenyl-2-oxotetrahydropyrimidin-1-yl]benzoate (1.82 g, 3.1 mmol) in ethanol-DMF (70 mL-30 mL) was added 10% palladium-carbon (0.4 g), and the resulting solution was stirred under a hydrogen atmosphere for 4 hours at room temperature. The resulting solution was filtered through Celite, and ethanol was evaporated under reduced pressure so as to give a DMF (30 mL) solution. To this solution was added 2-chloro-5-nitropyridine (0.52 g, 3.3 mmol) and stirred under a nitrogen atmosphere for 14 hours at room temperature, and then for 3 hours at 40° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 1.8 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=7.1 Hz), 2.14 (3H, s), 2.21-2.40 (2H, m), 3.75-3.97 (4H, m), 4.36 (2H, q, J=7.1 Hz), 7.01 (1H, d, J=9.1 Hz), 7.06 (1H, d, J=8.6 Hz), 7.23 (1H, dd, J=2.6 Hz, 8.6 Hz), 7.32 (1H, d, J=2.6 Hz), 7.40-7.49 (2H, m), 7.97-8.07 (2H, m), 8.46 (1H, dd, J=2.8 Hz, 9.1 Hz), 9.04 (1H, d, J=2.8 Hz).

Reference Example 261 Production of 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionic acid

To a solution of 2-chloro-5-nitropyridine (1.74 g, 11.0 mmol) and 4-mercaptohydrocinnamic acid (2.00 g, 11.0 mmol) in DMF (30 mL) was added potassium carbonate (4.55 g, 32.9 mmol), and the resulting solution was stirred for 1 hour at 80° C. To the reaction solution were added water and concentrated hydrochloric acid, and then cooled with ice. The precipitated solid matter was collected by filtration, to thereby yield 3.29 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (DMSO-d₆) δ 2.60 (2H, t, J=7.5 Hz), 2.91 (2H, t, J=7.5 Hz), 7.07 (1H, d, J=9.0 Hz), 7.43 (2H, d, J=8.2 Hz), 7.57 (2H, d, J=8.2 Hz), 8.39 (1H, dd, J=2.8 Hz, 9.0 Hz), 9.17 (1H, d, J=2.8 Hz), 12.19 (1H, s).

Reference Example 262 Production of ethyl 3-[3-methoxy-4-(5-nitropyridin-2-ylamino)phenyl]propionate

To 2-chloro-5-nitropyridine (3.11 g, 20 mmol) were added ethyl 3-(4-amino-3-methoxyphenyl)propionate (4.38 g, 20 mmol) and acetic acid (10 mL), and the resulting solution was stirred for 13 hours at 100° C. To the reaction solution were added ethyl acetate and water. The ethyl acetate layer was separated, washed with brine, a saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 3.78 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7.1 Hz), 2.61-2.67 (2H, m), 2.93-2.99 (2H, m), 3.89 (3H, s), 4.15 (2H, q, J=7.1 Hz), 6.73 (1H, d, J=9.2 Hz), 6.81-6.87 (2H, m), 7.43 (1H, brs), 7.92 (1H, d, J=8.1 Hz), 8.23 (1H, dd, J=9.2 Hz, 2.8 Hz), 9.11 (1H, d, J=2.8 Hz).

The following compounds were produced in the same manner as in Reference Example 262.

TABLE 38

Reference Example No. R₁₉₂ ¹H NMR (solvent) δppm 263 —COOC₂H₅ (DMSO-d₆) 1.32(3H, t, J = 7.1 Hz), 4.29(2H, q, J = 7.1 Hz), 7.01(1H, d, J = 9.3 Hz), 7.89(2H, d, J = 8.9 Hz), 8.36(1H, dd, J = 2.9 Hz, 9.3 Hz), 9.09(1H, d, J = 2.9 Hz), 10.43(1H, s). 264 —(CH₂)₂COOC₂H₅ (CDCl₃) 1.25(3H, t, J = 7.1 Hz), 2.64(2H, t, J = 7.6 Hz), 2.97(2H, t, J = 7.6 Hz), 4.14(2H, q, J = 7.1 Hz), 6.73(1H, d, J = 9.3 Hz), 7.20-7.40(4H, m), 8.23(1H, dd, J = 2.7 Hz, 9.3 Hz), 9.07(1H, d, J = 2.7 Hz). 265

(CDCl₃) 1.30(3H, t, J = 7.1 Hz), 2.77(4H, t, J = 5.0 Hz), 3.28(4H, t, J = 5.0 Hz), 3.28(2H, s), 4.22(2H, q, J = 7.1 Hz), 6.61(1H, d, J = 9.4 Hz), 6.95(2H, d, J = 9.0 Hz), 7.11(1H, brs), 7.22(2H, d, J = 9.0 Hz), 8.18(1H, dd, J = 9.4 Hz, 2.5 Hz), 9.05(1H, d, J = 2.5 Hz). 266

(CDCl₃) 1.28(3H, t, J = 7.1 Hz), 1.32-1.60(2H, m), 1.75- 2.12(3H, m), 2.29(2H, d, J = 6.9 Hz), 2.77(2H, td, J = 12.4 Hz, 2.4 Hz), 3.68(2H, d, J = 12.4 Hz), 4.16(2H, q, J = 7.1 Hz), 6.60(1H, d, J = 9.2 Hz), 6.96(2H, d, J = 8.9 Hz), 7.16(1H, brs), 7.20(2H, d, J = 8.9 Hz), 8.18(1H, dd, J = 9.2 Hz, 2.6 Hz), 9.05(1H, d, J = 2.6 Hz).

Reference Example 267 Production of 4-[(5-nitro-2-pyridyl)oxy]benzaldehyde ethylene acetal

To a solution of 4-[(5-nitro-2-pyridyl)oxy]benzaldehyde (5.00 g, 20.5 mmol) in benzene (100 mL) were added ethylene glycol (2.28 mL, 41.0 mmol) and p-toluenesulfonic acid (0.50 g), and the resulting solution was heated to reflux for 3 hours while removing water with a Dean-Stark. The reaction solution was washed with a saturated sodium bicarbonate solution, and subsequently washed with brine. The benzene layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 5.88 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 4.00-4.19 (4H, m), 5.83 (1H, s), 7.00 (1H, d, J=9.0 Hz), 7.15 (2H, d, J=8.5 Hz), 7.55 (2H, d, J=8.5 Hz), 8.45 (1H, dd, J=9.0 Hz, 2.0 Hz), 9.01 (1H, d, J=2.0 Hz).

The following compound was produced in the same manner as in Reference Example 267.

Reference Example 268 4-(2-Fluoro-4-nitrophenoxybenzaldehyde ethylene acetal

¹H NMR (DMSO-d₆) δ 3.90-4.10 (4H, m), 5.76 (1H, s), 7.15-7.25 (3H, m), 7.54 (2H, d, J=8.7 Hz), 8.10 (1H, ddd, J=1.3 Hz, 2.7 Hz, 9.1 Hz), 8.35 (1H, dd, J=2.7 Hz, 10.8 Hz).

Reference Example 269 Production of t-butyl [4-(5-nitropyridin-2-yloxy)phenyl]carbamate

To a solution of 4-(5-nitropyridin-2-yloxy)phenylamine (2.97 g, 12.85 mmol) in THF was added di-t-butyl dicarbonate (5.60 g, 25.66 mmol), and the resulting solution was stirred under reflux for 4 hours. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and to the resulting product was added diethyl ether. The obtained white powder was filtered, and the resulting product was washed with diethyl ether, to thereby yield 3.04 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 1.53 (9H, s), 6.53 (1H, brs), 7.00 (1H, d, J=9.2 Hz), 7.09 (2H, d, J=8.9 Hz), 7.45 (2H, d, J=8.9 Hz), 8.46 (1H, dd, J=9.2 Hz, 3.0 Hz), 9.03 (1H, d, J=3.0 Hz).

Reference Example 270 Production of 5-[3-methyl-4-(5-nitropyridin-2-yloxy)benzylidene]thiazolidine-2,4-dione

To a solution of 3-methyl-4-(5-nitropyridin-2-yloxy)benzaldehyde (600 mg, 2.32 mmol) in toluene (35 mL) were added 2,4-thiazolidinedione (270 mg, 2.31 mmol) and piperidine acetate (135 mg, 0.93 mmol). The resulting solution was attached to a Dean Stark, and stirred under reflux for 1.5 hours. After being left to cool for 17 hours at room temperature, the precipitated yellow powder was filtered, to thereby yield 600 mg of the title compound.

Appearance: Yellow powder

¹H NMR (DMSO-d₆) δ 2.15 (3H, s), 7.33 (1H, d, J=8.4 Hz), 7.35 (1H, d, J=9.1 Hz), 7.52 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.59 (1H, d, J=2.0 Hz), 7.79 (1H, s), 8.65 (1H, dd, J=9.1 Hz, 3.0 Hz), 9.02 (1H, d, J=3.0 Hz), 12.63 (1H, brs).

The following compounds were produced in the same manner as in Reference Example 270.

TABLE 39

Reference Example No. R₁₉₃ ¹H NMR (solvent) δppm 271

(DMSO-d₆) 7.35(1H, d, J = 9.0 Hz), 7.42(2H, d, J = 8.6 Hz), 7.71 (2H, d, J = 8.6 Hz), 7.84(1H, s), 8.65(1H, dd, J = 9.0 Hz, 2.9 Hz), 9.04(1H, d, J = 2.9 Hz), 12.64(1H, brs). 272 —CH═C(COOCH₃)₂ (CDCl₃) 3.87(6H, s), 7.09(1H, d, J = 9.0 Hz), 7.20(2H, d, J = 8.5 Hz), 7.53(2H, d, J = 8.5 Hz), 7.77(1H, s), 8.51(1H, dd, J = 9.0 Hz, 2.8 Hz), 9.04(1H, d, J = 2.8 Hz).

Reference Example 273 Production of N-[4-(2-fluoro-4-nitrophenoxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxyethyl]acetamide

To a solution of N-[4-(2-fluoro-4-nitrophenoxy)phenyl]acetamide (0.800 g, 2.76 mmol) in DMF (5 mL) was added 60% sodium hydride (0.118 g, 2.95 mmol). The resulting solution was stirred for 10 minutes at room temperature, after which a solution of 1-chloroacetyl-4-piperonylpiperazine (0.870 g, 2.96 mmol) in DMF (4 mL) was added to the reaction solution. The reaction solution was stirred for 2 hours at 60° C., and then for 1 hour at 100° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=5:1), to thereby yield 0.730 g of the title compound.

Appearance: Yellow oil

¹H NMR (DMSO-d₆) δ 1.82 (3H, s), 2.20-2.40 (4H, m), 3.30-3.50 (6H, m), 4.43 (2H, s), 5.98 (2H, s), 6.70-6.85 (3H, m), 7.20-7.30 (3H, m), 7.48 (2H, (f, J=8.8 Hz), 8.12 (1H, ddd, J=1.4 Hz, 2.7 Hz, 10.5 Hz), 8.36 (1H, dd, J=2.7 Hz, 10.7 Hz).

The following compound was produced in the same manner as in Reference Example 273.

Reference Example 274 3-(4-Benzyloxy-3-methylphenyl)-1-[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl]tetrahydropyrimidin-2-one

¹H NMR (DMSO-d₆) δ 1.92-2.08 (2H, m), 2.15 (3H, s), 2.22-2.40 (4H, m), 3.25-3.49 (8H, m), 3.56 (2H, d, J=5.6 Hz), 4.08 (2H, s), 5.09 (2H, s), 5.97 (2H, s), 6.74 (1H, dd J=1.3 Hz, 7.9 Hz), 6.84 (1H, d, J=7.9 Hz), 6.85 (1H, d, J=1.3 Hz), 6.91 (1H, d, J=8.7 Hz), 6.95 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.01 (1H, d, J=2.5 Hz), 7.28-7.34 (1H, m), 7.36-7.41 (2H, m), 7.42-7.48 (2H, m).

Reference Example 275 Production of 2-dimethylamino-N-[4-(5-nitropyridin-2-yloxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]acetamide

To a solution of 2-chloro-N-(4-(5-nitropyridin-2-yloxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]acetamide (0.300 g, 0.528 mmol) in acetonitrile (3 mL) was added at room temperature dimethylamine (0.150 mL, 1.63 mmol), and the resulting solution was stirred for 2 hours at 50° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol 10:1), to thereby yield 0.270 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 2.29 (6H, s), 2.40-2.45 (4H, m), 3.02 (2H, s), 3.40-3.46 (4H, m), 3.61 (2H, s), 4.48 (2H, s), 5.95 (2H, s), 6.70-6.77 (2H, m), 6.84 (1H, s), 7.09 (1H, d, J=9.0 Hz), 7.19 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.7 Hz), 8.51 (1H, dd, J=2.8 Hz, 9.0 Hz), 9.04 (1H, d, J=2.8 Hz).

Reference Example 276 Production of methyl 2-[4-(5-nitropyridin-2-yloxy)phenyl]propionate

To a solution of methyl 2-[4-(5-nitropyridin-2-yloxy)phenyl]acetate (0.50 g, 1.7 mmol) in DMF (10 mL) were added 60% sodium hydride (0.153 g, 3.8 mmol) and methyl iodide (0.13 mL, 2.1 mmol), and the resulting reaction solution was stirred for 1 hour at 0° C. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated aqueous sodium chloride. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=8:1), to thereby yield 0.32 g of the title compound.

Appearance: Colorless oil

¹H NMR (CDCl₃) δ 1.54 (3H, d, J=7.4 Hz), 3.69 (3H, s), 3.78 (1H, q, J=7.2 Hz), 7.03 (1H, d, J=9.1 Hz), 7.09-7.15 (2H, m), 7.36-7.41 (2H, m), 8.48 (1H, dd, J=9.1, 2.8 Hz), 9.05 (1H, d, J=2.8 Hz).

Reference Example 277 Production of ethyl 3-{3-methoxy-4-[methyl (5-nitropyridin-2-yl)amino]phenyl}propionate

To a solution of ethyl 3-[3-methoxy-4-(5-nitropyridin-2-ylamino)phenyl]propionate (3.70 g, 11 mmol) in DMF (60 mL) were added under ice-cooling sodium hydride (60%, 490 mg, 12 mmol) and methyl iodide (0.77 mL, 1.2 mmol), and the resulting reaction solution was stirred for 2 hours gradually warming up to room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, washed with water and brine, and then dried with anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 4.27 g of the title compound.

Appearance: Yellow oil substance

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.1 Hz), 2.66-2.71 (2H, m), 2.98-3.04 (2H, m), 3.46 (3H, s), 3.78 (3H, s), 4.17 (2H, q, J=7.1 Hz), 6.12 (1H, brd, J=9.5 Hz), 6.87-6.90 (2H, m), 7.11-7.14 (1H, m), 7.97-8.02 (1H, m), 9.11 (1H, d, J=2.7 Hz).

The following compounds were produced in the same manner as in Reference Example 277.

TABLE 40

Reference Example No. R₁₉₄ R₁₉₅ ¹H NMR (solvent) δppm 278 —CH₃ —COOC₂H₅ (DMSO-d₆) 1.34(3H, t, J = 7.1 Hz), 3.56(3H, s), 4.34(2H, q, J = 7.1 Hz), 6.70(1H, d, J = 9.5 Hz), 7.55(2H, d, J = 8.6 Hz), 8.06(2H, d, J = 8.6 Hz), 8.21(1H, dd, J = 2.8 Hz, 9.5 Hz), 9.05(1H, d, J = 2.8 Hz). 279 —CH₃ —(CH₂)₂COOC₂H₅ (CDCl₃) 1.26(3H, t, J = 7.1 Hz), 2.67(2H, t, J = 7.6 Hz), 3.01(2H, t, J = 7.6 Hz), 3.55(3H, s), 4.15(2H, q, J = 7.1 Hz), 6.32(1H, d, J = 9.5 Hz), 7.17(2H, d, J = 8.3 Hz), 7.32(2H, d, J = 8.3 Hz), 8.01(1H, dd, J = 2.7 Hz, 9.5 Hz), 9.11(1H, d, J = 2.7 Hz). 280 benzyl —(CH₂)₂COOC₂H₅ (CDCl₃) 1.24(3H, t, J = 7.2 Hz), 2.64(2H, t, J = 7.7 Hz), 2.97(2H, t, J = 7.7 Hz), 4.14(2H, q, J = 7.2 Hz), 5.27(2H, s), 6.26(1H, d, J = 9.5 Hz), 7.06(2H, d, J = 8.3 Hz), 7.20-7.30(7H, m), 8.02(1H, dd, J = 2.7 Hz, 9.5 Hz), 9.12(1H, d, J = 2.7 Hz). 281 —CH₃

(CDCl₃) 1.30(3H, t, J = 7.1 Hz), 2.78(4H, t, J = 5.0 Hz), 3.30(2H, s), 3.31(4H, t, J = 5.0 Hz), 3.53(3H, s), 4.22(2H, q, J = 7.1 Hz), 6.30(1H, d, J = 9.5 Hz), 6.99(2H, d, J = 8.9 Hz), 7.12(2H, d, J = 8.9 Hz), 7.99 (1H, dd, J = 9.5 Hz, 2.8 Hz), 9.10(1H, d, J = 2.8 Hz). 282 —CH₃

(CDCl₃) 1.28(3H, t, J = 7.1 Hz), 1.45(2H, qd, J = 12.2 Hz, 3.7 Hz), 1.80-2.17(3H, m), 2.30(2H, d, J = 6.9 Hz), 2.80(2H, td, J = 12.2 Hz, 2.3 Hz), 3.52(3H, s), 3.72(2H, d, J = 12.4 Hz), 4.16(2H, q, J = 7.1 Hz), 6.30(1H, d, J = 9.5 Hz), 6.98(2H, d, J = 8.9 Hz), 7.10(2H, d, J = 8.9 Hz), 7.98(1H, dd, J = 9.5 Hz, 2.8 Hz), 9.10(1H, d, J = 2.8 Hz).

TABLE 41

Reference Example No. R₁₉₆ ¹H NMR (CDCl₃) δppm 283 —(CH₂)₂CH₃ 0.93(3H, t, J = 7.4 Hz), 1.60-1.70(2H, m), 2.35-2.43(4H, m), 2.66(2H, t, J = 8.1 Hz), 3.03(2H, t, J = 8.1 Hz), 3.42(2H, s), 3.43- 3.45(2H, m), 3.62-3.65(2H, m), 3.96(2H, t, J = 7.7 Hz), 5.95(2H, s), 6.16(1H, d, J = 9.5 Hz), 6.70-6.80(2H, m), 6.84(1H, d. J = 1.3 Hz), 7.14(2H, d, J = 8.3 Hz), 7.33(2H, d, J = 8.3 Hz), 7.96(1H, dd, J = 2.8 Hz, 9.5 Hz), 9.08(1H, d, J = 2.8 Hz). 284 cyclopentyl 1.30-1.40(2H, m), 1.55-1.65(4H, m), 1.95-2.00(2H, m), 2.35- 2.45(4H, m), 2.67(2H, t, J = 7.4 Hz), 3.04(2H, t, J = 7.4 Hz), 3.42(2H, s), 3.43-3.47(2H, m), 3.55-3.68(2H, m), 5.18-5.28(1H, m), 5.88(1H, d, J = 9.5 Hz), 5.95(2H, s), 6.70-6.78(2H, m), 6.84(1H, s), 7.04(2H, d, J = 8.2 Hz), 7.34(2H, d, J = 8.2 Hz), 7.92(1H, dd, J = 2.8 Hz, 9.5 Hz), 9.09(1H, d, J = 2.8 Hz).

TABLE 42 Reference Example No. Chemical Structure ¹H NMR (solvent) δppm 285

(CDCl₃) 1.91-2.06(2H, m), 2.27(3H, s), 3.31-3.44 (2H, m), 3.58(2H, t, J = 6.3 Hz), 4.69-4.85(1H, m), 5.07(2H, s), 6.04(1H, s), 6.84(1H, d, J = 10.1 Hz), 7.01(1H, dd, J = 8.5 Hz, 2.5 Hz), 7.04 (1H, d, J = 2.5 Hz), 7.30-7.36(1H, m), 7.37- 7.46(4H, m). 286

(CDCl₃) 1.96-2.11(2H, m), 2.27(3H, s), 3.20-3.34 (2H, m). 3.56-3.68(2H, m), 4.50(2H, s), 5.07(2H, s), 5.94(2H, s), 6.72-6.80(2H, m), 6.84(1H, d, J = 8.6 Hz), 6.88(1H, d, J = 1.2 Hz), 7.04(1H, dd, J = 2.6 Hz, 8.6 Hz), 7.11(1H, d, J = 2.6 Hz), 7.28-7.34(1H, m), 7.35- 7.41(2H, m), 7.42-7.48(2H, m). 287

(DMSO-d₆) 3.20-3.40(2H, m), 3.71(3H, s), 3.64-3.83(2H, m), 4.36(2H, s), 6.84-6.95(2H, m), 7.22- 7.41(5H, m), 7.42-7.53(2H, m). 288

(DMSO-d₆) 2.18(3H, s), 3.35(2H, t, J = 8.7 Hz), 3.69-3.84(2H, m), 5.05(2H, s), 6.74(1H, s), 6.93(1H, d, J = 8.9 Hz), 7.23(1H, dd, J = 2.8 Hz, 8.9 Hz), 7.27-7.48(6H, m). 289

(CDCl₃) 2.29(3H, s), 3.28-3.39(2H, m), 3.68-3.81 (2H, m), 4.36(2H, s), 5.06(2H, s), 5.95(2H, s), 6.77(2H, s), 6.78-6.91(2H, m), 7.20-7.35(2H, m), 7.36-7.51(5H, m). 290

(CDCl₃) 1.93-2.12(2H, m), 2.27(3H, s), 3.28(2H, t. J = 5.9 Hz), 3.63(2H, t, J = 5.9 Hz), 3.88(6H, s), 4.55 (2H, s), 5.07(2H, s), 6.71-6.92(4H, m), 6.96-7.08 (1H, m), 7.11(1H, d, J = 2.1 Hz), 7.25-7.51(5H, m).

Reference Example 291 Production of N-[4-(5-nitropyridin-2-yloxy)phenyl]-2-(4-piperonylpiperazin-1-yl)acetamide

A solution of (4-piperonylpiperazin-1-yl)acetic acid (13.9 g, 50 mmol) was suspended in DMF (400 mL), and to the resulting suspension were added 1-hydroxybenzotriazole monohydrate (8.42 g, 55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.5 g, 55 mmol) and 4-(5-nitropyridin-2-yloxy)phenylamine (11.6 g, 50 mmol) under ice cooling. The resulting solution was stirred for 6 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was left for standing overnight at room temperature, and the resulting precipitated crystals were collected by suction filtration, to thereby yield 12.8 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.53 (4H, brs), 2.64-2.65 (4H, m), 3.15 (2H, s), 3.46 (2H, s), 5.95 (2H, s), 6.76 (2H, brs), 6.86 (1H, s), 7.04 (1H, d, J=9.1 Hz), 7.14 (2H, d, J=8.7 Hz), 7.67 (2H, d, J=8.9 Hz), 8.47 (1H, dd, J=9.1 Hz, 2.8 Hz), 9.03 (1H, d, J=2.8 Hz), 9.24 (1H, brs).

Reference Example 292 Production of ethyl{methanesulfonyl[ethoxy-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetate

A solution of ethyl [3-methoxy-4-(5-nitropyridin-2-yloxy)phenylamino]acetate (2.43 g, 7.00 mmol) was dissolved in THF (15 mL), dichloromethane (20 mL) and DMF (10 mL), and to the resulting solution were added triethylamine (1.95 mL, 13.99 mmol), dimethylaminopyridine (0.86 g, 7.00 mmol) and methanesulfonyl chloride (1.08 mL, 13.99 mmol) under ice cooling. The resulting solution was stirred for 14 hours at 30° C. Water was added to the reaction mixture, and extracted with dichloromethane. The dichloromethane layer was washed with water and brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to thereby yield 1.10 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 1.32 (3H, t, J=7.3 Hz), 3.18 (3H, s), 3.75 (3H, s), 4.26 (2H, q, J=7.3 Hz), 4.49 (2H, s), 7.09 (1H, d, J=9.1 Hz), 7.15 (2H, d, J=1.2 Hz), 7.25 (1H, s), 8.48 (1H, dd, J=9.1 Hz, 2.8 Hz), 8.98 (1H, d, J=2.8 Hz).

The following compounds were produced in the same manner as in Reference Example 292.

TABLE 43 Reference Example No. Chemical Structure ¹H NMR (solvent) δppm or MS 293

¹H NMR (DMSO-d₆) 3.00(3H, s), 5.17(2H, s), 7.05(1H, d, J = 8.4 Hz), 7.12(2H, d, J = 8.9 Hz), 7.19-7.26(4H, m), 7.67(2H, d, J = 8.9 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.5 Hz), 8.25(1H, d, J = 2.3 Hz), 9. 69(1H, brs). 294

¹H NMR (CDCl₃) 2.18(3H, s), 3.04(3H, s), 5.04(2H, s), 6.56(1H, brs), 6.96(1H, d, J = 8.6 Hz), 7.01-7.09(4H, m), 7.15(1H, d, J = 2.6 Hz), 7.56(2H, d, J = 8.4 Hz), 7.79(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.19(1H, d, J = 2.5 Hz). 295

MS 364(M⁺)

Reference Example 296 Production of 3-[4-(5-nitropyridin-2-yloxy)phenyl]-n-propanol

To a solution of 3-[4-(5-nitropyridin-2-yloxy)phenyl]propionic acid (2.64 g, 9.2 mmol) in THF (50 mL) was added dropwise a 1 M borane-THF complex THF solution (38.4 mL, 38.4 mmol) under ice cooling. The reaction solution was stirred for 2 hours at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and then brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, after which solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate 1:1), to thereby yield 1.17 g of the title compound.

Appearance: Green oil

¹H NMR (CDCl₃) δ 1.90-1.96 (2H, m), 2.73-2.79 (2H, m), 3.69-3.74 (2H, m), 7.00-7.09 (3H, m), 7.26-7.30 (2H, m), 8.44-8.49 (1H, m), 9.05 (1H, d, J=2.6 Hz).

Reference Example 297 Production of 2-{4-[3-(t-butyldimethylsilanyloxy)propyl]phenoxy}-5-nitropyridine

To a solution of 3-[4-(5-nitropyridin-2-yloxy)phenyl]-n-propanol (1.17 g, 4.3 mmol) in DMF (10 mL) were added imidazole (580 mg, 8.5 mmol) and t-butylchlorodimethylsilane (640 mg, 4.2 mmol), and the resulting solution was stirred for 13 hours at room temperature. Water was added to the reaction mixture, and extracted with diethyl ether, and the diethyl ether layer was washed with water and then brine. The diethyl ether layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.14 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 0.07 (6H, s), 0.92 (9H, s), 1.84-1.89 (2H, m), 2.69-2.75 (2H, m), 3.66 (2H, t, J=6.3 Hz), 6.99-7.08 (3H, m), 7.27 (2H, d, J=7.6 Hz), 8.46 (111, dd, J=8.9 Hz, 3.0 Hz), 9.05 (111, d, J=3.0 Hz).

The following compound was produced in the same manner as in Reference Example 297.

Reference Example 298 2-{4-[2-(t-Butyldimethylsilanyloxy)ethyl]phenoxy}-5-nitropyridine

¹H NMR (CDCl₃) δ 0.00 (6H, s), 0.88 (9H, s), 2.86 (2H, t, J=6.9 Hz), 3.84 (2H, t, J=6.9 Hz), 7.00 (1H, d, J=9.2 Hz), 7.05-7.08 (2H, m), 7.26-7.31 (2H, m), 8.46 (1H, dd, J=9.2 Hz, 3.0 Hz), 9.05 (1H, d, J=3.0 Hz).

Reference Example 299 Production of ethyl 4-[4-(5-nitropyridin-2-yloxy)phenyl]butanoate

To a solution of 4-[4-(5-nitropyridin-2-yloxy)phenyl]butanoic acid (9.98 g, 33.01 mmol) in dichloromethane were added ethanol (5.59 mL, 99.01 mmol), 4-dimethylaminopyridine (400 mg, 3.27 mmol), triethylamine (13.81 mL, 99.08 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.6 g, 39.65 mmol) under ice cooling, and the resulting solution was stirred for 20 minutes under ice cooling and then for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate, and the ethyl acetate layer was washed with 1 N hydrochloric acid, a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 6.77 g of the title compound.

Appearance: Colorless oil

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.0 Hz), 1.99 (2H, dt, J=15.0 Hz, 7.5 Hz), 2.36 (2H, t, J=7.5 Hz), 2.70 (2H, t, J=7.5 Hz), 4.14 (2H, q, J=7.0 Hz), 7.01 (1H, d, J=9.0 Hz), 7.08 (2H, d, J=8.5 Hz), 7.26 (2H, d, J=8.5 Hz), 8.46 (1H, dd, J=9.0 Hz, 3.0 Hz), 9.04 (1H, d, J=3.0 Hz).

Reference Example 300 Production of methyl 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionate

To a solution of 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionic acid (86.0 g, 0.283 mmol) in DMF (1 mL) were added potassium carbonate (59.0 mg, 0.424 mmol) and methyl iodide (0.0260 mL, 0.424 mmol), and the resulting solution was stirred for 1 hour at room temperature. Water was added to the reaction mixture, and then cooled with ice. The precipitated solid matter was collected by filtration, to thereby yield 76.9 mg of the title compound.

Appearance: Light brown powder

¹H NMR (DMSO-d₆) δ 2.70 (2H, t, J=7.6 Hz), 2.94 (2H, t, J=7.6 Hz), 3.60 (3H, s), 7.07 (1H, d, J=8.9 Hz), 7.43 (2H, d, J=8.1 Hz), 7.57 (2H, d, J=8.1 Hz), 8.39 (1H, dd, J=2.7 Hz, 8.9 Hz), 9.17 (1H, d, J=2.7 Hz).

Reference Example 301 Production of ethyl (Z)-3-[4-(5-nitro-2-pyridyloxy)phenyl]-2-butenoate

To a suspension of 60% sodium hydride (1.28 g, 32.0 mmol) in THF (80 mL) was added dropwise a solution of triethyl phosphonoacetate (8.71 g, 38.8 mmol) in THF (40 mL) under ice cooling, and the resulting solution was stirred for 10 minutes at the same temperature. To the reaction solution was added 4-[(5-nitro-2-pyridyl)oxy]acetophenone (5.90 g, 22.8 mmol) and the resulting solution was stirred at the same temperature for 10 minutes, and then stirred at room temperature for 60 hours. To the reaction solution was added saturated ammonium chloride and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution, and then washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.17 g of the title compound.

Appearance: Colorless needles

¹H NMR (CDCl₃) δ 1.13 (3H, t, J=7.1 Hz), 2.20 (3H, d, J=1.4 Hz), 4.02 (2H, q, J=7.1 Hz), 5.93 (1H, q, J=1.4 Hz), 7.02 (1H, d, J=9.0 Hz), 7.12 (2H, d, J=8.6 Hz), 7.29 (2H, d, J=8.6 Hz), 8.45 (1H, dd, J=9.0 Hz, 2.8 Hz), 9.03 (1H, d, J=2.8 Hz).

The following compounds were produced in the same manner as in Reference Example 301.

Reference Example 302 Ethyl (E)-3-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}acrylate

Melting point: 166-167° C.

TABLE 44

Reference Example No. R₁₉₇ R₁₉₈ ¹H NMR (CDCl₃) δppm or MS 303 —H —H ¹H NMR 1.35(3H, t, J = 7.1 Hz), 4.28(2H, q, J = 7.1 Hz), 6.43(1H, d, J = 16.0 Hz), 7.09(1H, d, J = 8.9 Hz), 7.20(2H, d, J = 8.7 Hz), 7.62(2H, d, J = 8.7 Hz), 7.70(1H, d, J = 16.0 Hz), 8.50(1H, dd, J = 8.9 Hz, 2.5 Hz), 9.04(1H, d, J = 2.5 Hz). 304 —H —CH₃ ¹H NMR 1.31(3H, t, J = 7.1 Hz), 2.58(3H, d, J = 1.2 Hz), 4.21(2H, q, J = 7.1 Hz), 6.14(1H, q, J = 1.2 Hz), 7.05(1H, d, J = 9.0 Hz), 7.16(2H, d, J = 8.7 Hz), 7.55(2H, d, J = 8.7 Hz), 8.48(1H, dd, J = 9.0 Hz, 2.8 Hz), 9.03(1H, d, J = 2.8 Hz). 305 —CH₃ —H MS 328(M⁺)

Reference Example 306 Production of ethyl 3-[4-(5-nitropyridine-2-carbonyl)phenyl]propionate

A solution of bis(tributyltin) (1.37 g, 2.36 mmol) in toluene (7 mL) was added under an argon atmosphere to 2-chloro-5-nitropyridine (0.325 g, 2.05 mmol), bis(dibenzylideneacetone)palladium (0) (18.1 mg, 0.0315 mmol), tri(2-furyl)phosphine (29.3 mg, 0.126 mmol) and molecular sieves 4A (1.90 g), and the resulting solution was heated to reflux for 1 hour. To the reaction solution was added bis(dibenzylideneacetone)palladium (0) (27.2 mg, 0.0472 mmol) and tri(2-furyl)phosphine (43.9 mg, 0.189 mmol), and subsequently added a solution of 4-[2-ethoxycarbonyl]ethyl]benzoyl chloride (0.379 g, 1.57 mmol) in toluene (5 mL). The resulting reaction solution was stirred for 4 hours at 80° C. To the reaction solution was added saturated aqueous potassium fluoride and stirred for 0.5 hours at room temperature. Insoluble matter was then filtered off. The filtrate was extracted with ethyl acetate, and the ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane→n-hexane:ethyl acetate=4:1), to thereby yield 0.323 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7.1 Hz), 2.65 (2H, t, 7.7 Hz), 3.03 (2H, t, J=7.7 Hz), 4.12 (2H, q, J=7.1 Hz), 7.34 (2H, d, J=8.3 Hz), 8.00 (2H, d, J=8.3 Hz), 8.18 (1H, d, J=8.5 Hz), 8.65 (1H, dd, J=8.5 Hz, 2.6 Hz), 9.49 (1H, d, J=2.6 Hz).

Reference Example 307 Production of ethyl 3-[4-(4-aminophenoxy)phenyl]propionate

To a suspension of 5% palladium-carbon (0.50 g) in ethanol (50 mL) was added ethyl 3-[4-(4-nitrophenoxy)phenyl]propionate (5.00 g, 15.9 mmol), and the resulting solution was subjected to catalytic reduction at atmospheric pressure and at room temperature. Once the absorption of hydrogen had stopped, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 4.52 g of the title compound.

Appearance: Light brown oil

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7.1 Hz), 2.57 (2H, t, J=7.8 Hz), 2.88 (2H, t, J=7.8 Hz), 3.55 (2H, brs), 4.10 (2H, q, J=7.1 Hz), 6.64 (2H, d, J=8.8 Hz), 6.78-6.86 (4H, m), 7.08 (2H, d, J=8.6 Hz).

The following compounds were produced in the same manner as in Reference Example 307.

TABLE 45

Reference Example No. R₁₉₉ R₂₀₀ ¹H NMR (CDCl₃) δppm 308 4-NH₂Ph— 2-(CH₂)₂COOCH₃ 2.66(2H, t, J = 7.8 Hz), 3.00(2H, t, J = 7.8 Hz), 3.54 (2H, brs), 3.63(3H, s), 6.65(2H, d, J = 8.8 Hz), 6.70 (1H, d, J = 8.1 Hz), 6.79(2H, d, J = 8.8 Hz), 6.94(1H, t, J = 8.1 Hz), 7.08(1H, t, J = 8.1 Hz), 7.19(1H, d, J = 8.1 Hz). 309 4-NH₂Ph— 3-(CH₂)₂COOC₂H₅ 1.21(3H, t, J = 7.2 Hz), 2.56(2H, t, J = 7.9 Hz), 2.87 (2H, t, J = 7.9 Hz), 3.54(2H, brs), 4.10(2H, q, J = 7.2 Hz), 6.66(2H, d, J = 8.8 Hz), 6.70-6.76(2H, m), 6.79-6.87(3H, m), 7.16(1H, t, J = 7.8 Hz). 310 2-NH₂Ph— 4-(CH₂)₂COOC₂H₅ 1.22(3H, t, J = 7.2 Hz), 2.56(2H, t, J = 7.8 Hz), 2.89 (2H, t, J = 7.8 Hz), 3.55(2H, brs), 4.11(2H, q, J = 7.2 Hz), 6.72(1H, t, J = 7.8 Hz), 6.79-6.92(4H, m), 6.93 (1H, t, J = 7.8 Hz), 7.12(2H, d, J = 8.5 Hz). 311 4-NH₂Ph— 4-COOC₂H₅ 1.37(3H, t, J = 7.1 Hz), 4.36(2H, q, J = 7.1 Hz), 4.00-4.50(2H, m), 6.78(2H, d, J = 8.9 Hz), 6.89-6.95 (4H, m), 7.97(2H, d, J = 8.9 Hz). 312 3-NH₂Ph— 4-(CH₂)₂COOC₂H₅ 1.22(3H, t, J = 7.2 Hz), 2.59(2H, t, J = 7.8 Hz), 2.91 (2H, t, J = 7.8 Hz), 3.65(2H, brs), 4.12(2H, q, J = 7.2 Hz), 6.29(1H, t, J = 2.2 Hz), 6.32-6.41(2H, m), 6.92 (2H, d, J = 8.6 Hz), 7.06(1H, t, J = 8.0 Hz), 7.13(2H, d, J = 8.6 Hz). 313

3-COOCH₃ 3.56(2H, brs), 3.89(3H, s), 6.80(1H, dd, J = 8.6 Hz, 0.7 Hz), 7.11(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.25-7.29 (1H, m), 7.39-7.44(1H, m), 7.69-7.72(2H, m), 7.78-7.82(1H, m).

TABLE 46

Reference Example No. R₂₀₁ Form ¹H NMR (solvent) δppm 314 —Ac hydrochloride (DMSO-d₆) 2.53(3H, s), 3.30-4.20(3H, m), 6 88(1H, d, J = 8.8 Hz), 6.99-7.05(3H, m), 7.22(1H, t, J = 8.8 Hz), 7.96(1H, d, J = 8.9 Hz). 315 —CH₂COOCH₃ free (CDCl₃) 3.57(2H, s), 3.60-3.80(5H, m), 6.41(1H, ddd, J = 1.2 Hz, 2.6 Hz, 8.6 Hz), 6.50(1H, dd, J = 2.6 Hz, 12.0 Hz), 6.80- 6.95(3H, m), 7.18(2H, d, J = 8.4 Hz). 316 —(CH₂)₂COOC₂H₅ free (CDCl₃) 1.21(3H, t, J = 7.1 Hz), 2.56(2H, t, J = 7.8 Hz), 2.87(2H, t, J = 7.8 Hz), 3.66(2H, brs), 4.10(2H, q, J = 7.1 Hz), 6.34-6.43(1H, m), 6.48(1H, dd, J = 12.0 Hz, 2.7 Hz), 6.77- 6.93(3H, m), 7.08(2H, d, J = 8.7 Hz). 317 —H free (CDCl₃) 3.66(2H, brs), 6.35-6.44(1H, m), 6.49(1H, dd, J = 12.0 Hz, 2.7 Hz), 6.83- 6.96(3H, m), 7.01(1H, dd, J = 9.0 Hz, 8.0 Hz), 7.26(2H, t, J = 8.0 Hz). 318 —(CH₂)₃COOC₂H₅ free (CDCl₃) 1.23(3H, t, J = 7.1 Hz), 1.83- 1.97(2H, m), 2.28(2H, t, J = 7.5 Hz), 2.57(2H, t, J = 7.6 Hz), 3.66(2H, brs), 4.09(2H, q, J = 7.1 Hz), 6.34-6.43(1H, m), 6.48(1H, dd, J = 12.0 Hz, 2.7 Hz), 6.81(2H, d, J = 8.5 Hz), 6.88(1H, dd, J = 9.0 Hz, 8.0 Hz), 7.05(2H, d, J = 8.5 Hz). 319 —COOC₂H₅ free (DMSO-d₆) 1.29(3H, t, J = 7.1 Hz), 4.27(2H, q, J = 7.1 Hz), 5.42(2H, brs), 6.41(1H, dt, J = 1.6 Hz, 8.6 Hz), 6.50(1H, dd, J = 2.5 Hz, 13.3 Hz), 6.90-7.00(3H, m), 7.91(2H, d, J = 9.7 Hz). 320 —NHCH₂COOC₂H₅ free (CDCl₃) 1.29(3H, t, J = 7.1 Hz), 3.62(2H, s), 3.86(2H, s), 4.12(1H, s), 4.23(2H, q, J = 7.1 Hz), 6.35-6.39(1H, m), 6.48(1H, dd, J = 2.7 Hz, 12.1 Hz), 6.55(2H, d, J = 8.9 Hz), 6.80- 6.85(3H, m). 321

free (CDCl₃) 3.70(2H, brs), 3.95-4.15(4H, m), 5.76(1H, s), 6 38-6.42(1H, m), 6.49(1H, dd, J = 2.7 Hz, 14.7 Hz), 6.85-6.93(3H, m), 7.39(2H, d, J = 8.7 Hz).

TABLE 47

Reference Example No. R₂₀₂ R₂₀₃ R₂₀₄ ¹H NMR (CDCl₃) δppm 322 —H —H —C₂H₅ 1.38(3H, t, J = 7.3 Hz), 4.35(2H, q, J = 7.3 Hz), 6.82(1H, d, J = 8.6 Hz), 7.04-7.14(3H, m), 7.75(1H, d, J = 3.0 Hz), 8.01-8.04(2H, m). 323 —H —H —CH₃ 3.30 (2H, brs), 3.89(3H, s), 6.82(1H, d, J = 8.6 Hz), 7.04-7.13 (3H, m), 7.75(1H, d, J = 3.0 Hz), 8.02(2H, dd, J = 6.6 Hz, 2.0 Hz). 324 —F —H —CH₃ 3.57(2H, brs), 3.91(3H, s), 6.87(1H, d, J = 8.6 Hz), 7.10-7.23(2H, m), 7.64(1H, d, J = 3.0 Hz), 7.80- 7.82(1H, m), 7.83-7.85(1H, m). 325 —F —H —C₂H₅ 1.38(3H, t, J = 7.1 Hz), 4.37(2H, q, J = 7.1 Hz), 6.87(1H, d, J = 8.6 Hz), 7.12(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.15-7.22(1H, m), 7.64(1H, d, J = 3.0 Hz), 7.81- 7.86(2H, m). 326 —CH₃ —H —CH₃ 2.29(3H, s), 3.56(2H, brs), 3.89(3H, s), 6.79(1H, d, J = 8.6 Hz), 6.92(1H, d, J = 8.6 Hz), 7.11(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.71(1H, d, J = 3.0 Hz), 7.85(1H, dd, J = 8.6 Hz, 2.4 Hz), 7.94(1H, d, J = 2.4 Hz). 327 —OCH₃ —H —C₂H₅ 1.38(3H, t, J = 7.1 Hz), 3.55(2H, brs), 3.85(3H, s), 4.37(2H, q, J = 7.1 Hz), 6.79-6.83(1H, m), 7.02- 7.10(2H, m), 7.63-7.67(3H, m). 328 —H —OCH₃ —CH₃ 3.63(2H, brs), 3.86(6H, s), 6.54-6.58(1H, m), 6.68(1H, d, J = 2.2 Hz), 6.81-6.84(1H, m), 7.13(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.77(1H, dd, J = 3.0 Hz, 0.5 Hz), 7.83(1H, d, J = 8.9 Hz). 329 —H —CH₃ —CH₃ 2.58(3H, s), 3.63(2H, brs), 3.86(3H, s), 6.80-6.88(3H, m), 7.13(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.75(1H, d, J = 3.0 Hz), 7.92-7.96(1H, m). 330 —Cl —H —CH₃ 3.62(2H, brs), 3.91(3H, s), 6.88(1H, d, J = 8.6 Hz), 7.08-7.15(2H, m), 7.68(1H, d, J = 3.0 Hz), 7.91(1H, dd, J = 8.6 Hz, 2.1 Hz), 8.13(1H. d, J = 2.1 Hz).

TABLE 48

Reference Example No. R₂₀₅ R₂₀₆ M ¹H NMR (CDCl₃) δppm or MS 331 —H —CH₃ 2 MS 272(M⁺) 332 —OCH₃ —C₂H₅ 2 ¹H NMR 1.25(3H, t, J = 7.1 Hz), 2.63(2H, t, J = 7.5 Hz), 2.94(2H, t, J = 7.5 Hz), 3.43(2H, brs), 3.77(3H, s), 4.14(2H, q, J = 7.1 Hz), 6.71-6.86(3H, m), 6.98(1H, d, J = 8.0 Hz), 7.06(1H, dd, J = 8.6 Hz, 2.9 Hz), 7.60(1H, d, J = 2.9 Hz). 333 —H —CH₃ 1 ¹H NMR 3.60(2H, s), 3.69(3H, s), 6.76(1H, d, J = 8.6 Hz), 6.99-7.10 (3H, m), 7.24-7.27(2H, m), 7.71(1H, d, J = 3.0 Hz). 334 —H —C₂H₅ 2 ¹H NMR 1.21(3H, t, J = 7.1 Hz), 2.58(2H, t, J = 7.7 Hz), 2.90(2H, t, J = 7.7 Hz). 4.11(2H, q, J = 7.1 Hz), 6.72(1H, d, J = 8.6 Hz), 6.95(2H, d, J = 8.5 Hz), 7.05(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.14(2H, d, J = 8.5 Hz), 7.68(1H, d, J = 3.0 Hz). 335 —OCH₃ —CH₃ 2 ¹H NMR 2.62-2.68(2H, m), 2.91-2.97(2H, m), 3.45(2H, brs), 3.69(3H, s), 3.77(3H, s), 6.74-6.79(2H, m), 6.82(1H, d, J = 1.8 Hz), 6.98(1H, d. J = 7.9 Hz), 7.04-7.26(1H, m), 7.64(1H, d, J = 3.0 Hz). 336 —OC₂H₅ —C₂H₅ 2 ¹H NMR 1.20(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz), 2.51-2.68 (2H, m), 2.81-3.01(2H, m), 3.19-3.63(2H, m), 3.98(2H, q, J = 7.0 Hz), 4.14(2H, q, J = 7.1 Hz), 6.69- 6.83(3H, m), 6.95-7.09(2H, m), 7.60-7.67(1H, m). 337 —F —C₂H₅ 2 ¹H NMR 1.25(3H, t, J = 7.1 Hz), 2.52-2.71(2H, m), 2.86- 3.02(2H, m), 3.47(2H, brs), 4.14(2H, q, J = 7.1 Hz), 6.81(1H, d, J = 8.6 Hz), 6.93-7.04(2H, m), 7.05-7.13(2H, m), 7.63(1H, d, J = 2.9 Hz). 338 —H —C₂H₅ 4 ¹H NMR 1.25(3H, t, J = 7.2 Hz), 1.55-1.80(4H, m), 2.32(2H, t, J = 7.0 Hz), 2.60(2H, t, J = 7.0 Hz), 3.49(2H, brs), 4.12(2H, q, J = 7.2 Hz), 6.74(1H, d, J = 8.5 Hz), 6.97(2H, d, J = 8.5 Hz), 7.06(1H, dd, J = 8.5 Hz, 3.0 Hz), 7.14(2H, d, J = 8.5 Hz), 7.71(1H, d, J = 3.0 Hz). 339 —H —C₂H₅ 3 ¹H NMR 1.26(3H, t, J = 7.5 Hz), 1.94(2H, dt, J = 15.0 Hz, 7.5 Hz), 2.33(2H, t, J = 7.5 Hz), 2.63(2H, t, J = 7.5 Hz), 3.50(2H, brs), 4.13 (2H, q, J = 7.0 Hz), 6.75(1H, d, J = 8.5 Hz), 6.98(2H, d, J = 8.5 Hz), 7.07(1H, dd, J = 8.5 Hz, 3.0 Hz), 7.15(2H, d, J = 8.5 Hz), 7.72(1H, d, J = 3.0 Hz).

TABLE 49

Reference Example No. Xa₈ M Form ¹H NMR (solvent) δppm 340 —NH— 2 free (CDCl₃) 1.24(3H, t, J = 7.1 Hz), 2.60(2H, t, J = 7.6 Hz), 2.90(2H, t, J = 7.6 Hz), 3.35(2H, brs), 4.13(2H, q, J = 7.1 Hz), 6.16(1H, brs), 6.77(1H, d, J = 8.6 Hz), 6.98(1H, dd, J = 2.9 Hz, 8.6 Hz), 7.00- 7.15(4H, m), 7.78(1H, d, J = 2.9 Hz). 341 —N(CH₃)— 0 hydrochloride (DMSO-d₆) 1.30(3H, t, J = 7.1 Hz), 3.43(3H, s), 4.23 (2H, q, J = 7.1 Hz), 7.03(1H, d, J = 9.1 Hz), 7.30(2H, d, J = 8.6 Hz), 7.55(1H, d, J = 9.1 Hz), 7.93(2H, d, J = 8.6 Hz), 8.05(1H, s). 342 —N(CH₃)— 2 free (CDCl₃) 1.24(3H, t, J = 7.2 Hz), 2.63(2H, t, J = 7.7 Hz), 2.95(2H, t, J = 7.7 Hz), 3.53(3H, s), 4.14(2H, q, J = 7.2 Hz), 6.52(1H, d, J = 9.5 Hz), 7.07(1H, dd, J = 2.7 Hz, 9.5 Hz), 7.10(2H, d, J = 8.3 Hz), 7.22(2H, d, J = 8.3 Hz), 7.83(1H, d, J = 2.7 Hz). 343 —N(CH₂Ph)— 2 dihydrochloride (CDCl₃) 1.22(3H, t, J = 7.1 Hz), 2.57(2H, t, J = 7.7 Hz), 2.90(2H, t, J = 7.7 Hz), 4.11(2H, q, J = 7.1 Hz), 5.28 (2H, s), 6.65(1H, d, J = 8.8 Hz), 7.08(2H, d, J = 7.8 Hz), 7.15-7.24(7H, m), 8.27(1H, d, J = 8.8 Hz), 8.80(lH, s). 344 —CO— 2 free (CDCl₃) 1.21(3H, t, J = 7.1 Hz), 2.63(2H, t, J = 7.7 Hz), 2.98(2H, t, J = 7.7 Hz), 4.10(2H, q, J = 7.1 Hz), 7.18 (2H, brs), 7.27(2H, d, J= 8.1 Hz), 7.32(1H, d, J = 8.3 Hz), 7.88-7.99(3H, m), 8.27(1H, s). (—CO— means a group of

Hereinafter —CO— indicates the same meaning.)

TABLE 50

Reference Example No. R₂₀₇ R₂₀₈ R₂₀₉ M ¹H NMR (solvent) δppm 345 —H —H —C(CH₃)₃ 0 (CDCl₃) 1.51(9H, s), 3.49(2H, brs), 6.41(1H, brs), 6.72(1H, d, J = 8.6 Hz), 7.00(2H, d, J = 8.9 Hz), 7.06(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.32(2H, d, J = 8.9 Hz), 7.69(1H, d, J = 3.0 Hz). 346 —H —Ac —C₂H₅ 1 (CDCl₃) 1.27(3H, t, J = 7.1 Hz), 1.94(3H, s), 3.60(2H, brs), 4.18(2H, q, J = 7.1 Hz), 4.35(2H, s), 6.82(1H, d, J = 8.6 Hz), 7.07(2H, d, J = 8.8 Hz), 7.12(1H, dd, J = 3.0 Hz, 8.6 Hz), 7.31(2H, d, J = 8.8 Hz), 7.73(1H, d, J = 3.0 Hz). 347 —H —Ac —C₂H₅ 2 (CDCl₃) 1.23(3H, t, J = 7.1 Hz), 1.85(3H, s), 2.57(2H, t, J = 7.4 Hz), 3.60(2H, s), 3.98(2H, t, J = 7.4 Hz), 4.07(2H, q, J = 7.1 Hz), 6.82(1H, d, J = 8.6 Hz), 7.08(2H, d, J = 8.8 Hz), 7.10-7.15 (3H, m), 7.74(1H, d, J = 3.0 Hz). 348 —CH₃ —Ac —C₂H₅ 1 (CDCl₃) 1.28(3H, t, J = 7.1 Hz), 1.95(3H, s), 2.23(3H, s), 3.52(2H, s), 4.19(2H, q, J = 7.1 Hz), 4.34(2H, s), 6.73(1H, d, J = 8.6 Hz), 6.91(1H, d, J = 8.4 Hz), 7.05-7.15(2H, m), 7.20(1H, s), 7.66(1H, s). 349 —H —CH₃ —CH₃ 1 (CDCl₃) 3.05(3H, s), 3.45(2H, brs), 3.72(3H, s), 4.05(2H, s), 6.67(3H, d, J = 9.0 Hz), 6.98(2H, d, J = 2.0 Hz), 7.04(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.69(1H, d, J = 2.0 Hz). 350 —H —CH₃ —C₂H₅ 1 (CDCl₃) 1.25(3H, t, J = 7.1 Hz), 3.05(3H, s), 3.45(2H, brs), 4.03(2H, s), 4.18(2H, q, J = 7.1 Hz), 6.65-6.69(3H, m), 6.96 (2H, d, J = 9.0 Hz), 7.04(1H, dd, J = 2.9 Hz, 8.6 Hz), 7.69(1H, d, J = 2.9 Hz). 351 —H —C₂H₅ —C₂H₅ 1 (CDCl₃) 1.20(3H, t, J = 7.2 Hz), 1.26(3H, t, J = 7.2 Hz), 3.40-3.46(4H, m), 3.99(2H, s), 4.19(2H, q, J = 7.2 Hz), 6.63 (2H, d, J = 9.1 Hz), 6.67(1H, d, J = 8.6 Hz), 6.95(2H, d, J = 9.1 Hz), 7.04(1H, dd, J = 3.2 Hz, 8.6 Hz), 7.69(1H, d, J = 3.2 Hz). 352 —CH₃ —CH₃ —C₂H₅ 1 (CDCl₃) 1.26(3H, t, J = 7.1 Hz), 2.13(3H, s), 3.05(3H, s), 3.41(2H, brs), 4.02(2H, s), 4.19(2H, q, J = 7.1 Hz), 6.46-6.68 (3H, m), 6.89(1H, d, J = 8.6 Hz), 7.03(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.67(1H, d, J = 3.0 Hz). 353 —OCH₃ —CH₃ —C₂H₅ 1 (CDCl₃) 1.26(3H, t, J = 7.1 Hz), 3.07(3H, s), 3.42(2H, brs), 3.75(3H, s), 4.04(2H, s), 4.19(2H, q, J = 7.1 Hz), 6.24(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.33(1H, d, J = 2.8 Hz), 6.67(1H, d, J = 8.6 Hz), 6.95(1H, d, J = 8.7 Hz), 7.02(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.63(1H, d, J = 2.8 Hz). 354 —OCH₃ —C₂H₅ —C₂H₅ 1 (DMSO-d₆) 1.13(3H, t, J = 7.1 Hz), 1.20(3H, t, J = 7.1 Hz), 3.41(2H, q, J = 7.1 Hz), 3.63(3H, s), 4.09-4.17(4H, m), 4.81 (2H, brs), 6.11(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.26(1H, d, J = 2.8 Hz), 6.55(1H, d, J = 8.6 Hz), 6.79(1H, d, J = 8.7 Hz), 6.99(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.40(1H, d, J = 2.3 Hz).

TABLE 51

Reference Example No. R₂₁₀ ¹H NMR (CDCl₃) δppm 355

1.48(9H, s), 3.04(4H, t, J = 5.0 Hz), 3.54(2H, brs), 3.57(4H, t, J = 5.0 Hz), 6.65(2H, d, J = 9.0 Hz), 6.82(2H, d, J = 9.0 Hz), 6.88(4H, ABq, J = 9.0 Hz). 356

1.78(2H, m), 2.03(2H, m), 2.86(2H, m), 3.39(3H, s), 3.42(2H, m), 3.52(2H, brs), 3.70(1H, m), 4.72(2H, s), 6.64(2H, d, J = 9.0 Hz), 6.82(2H, d, J = 9.0 Hz), 6.88(4H, ABq, J = 9.0 Hz). 357

1.27(3H, t, J = 7.0 Hz), 1.88(2H, dq, J = 3.5 Hz, 12.5 Hz), 2.03(2H, dd, J = 12.5 Hz, 3.0 Hz), 2.40(1H, m), 2.72(2H, dt, J = 2.5 Hz, 12.0 Hz), 3.51-3.53(4H, m), 4.16(2H, q, J = 7.0 Hz), 6.65(2H, d, J = 8.5 Hz), 6.82(2H, d, J = 8.5 Hz), 6.88(4H, s). 358

1.48(9H, s), 1.74(2H, brd, J = 11.5 Hz), 1.85(2H, m), 2.74(2H, m), 2.77(3H, s), 3.53(2H, brs), 3.60(2H, brd, J = 12.0 Hz), 4.12(1H, brs), 6.65(2H, d, J = 8.5 Hz), 6.82(2H, d, J = 8.5 Hz), 6.87(4H, s). 359

1.30(3H, t, J = 7.0 Hz), 1.81(2H, m), 2.03(2H, m), 2.84(1H, m), 2.95(1H, m), 3.35(1H, m), 3.44(1H, m), 3.54(3H, m), 4.15(2H, s), 4.23(2H, q, J = 7.0 Hz), 6.65(2H, d, J = 9.0 Hz), 6.82(2H, d, J = 9.0 Hz), 6.88(4H, s). 360

1.48(9H, s), 1.60(2H, m), 1.80(2H, m), 2.59(1H, m), 2.78(2H, brs), 3.57(2H, brs), 4.23(2H, brs), 4.12(1H, brs), 6.67(2H, d, J = 9.0 Hz), 6.86(2H, d, J = 9.0 Hz), 6.87(2H, d, J = 9.0 Hz), 7.09(2H, d, J = 9.0 Hz).

TABLE 52

Reference Example No. R₂₁₁ R₂₁₂ ¹H NMR (CDCl₃) δ ppm or MS 361 —H —Ac ¹H NMR 2.50 (3H, s), 3.60 (2H, brs), 6.80-7.90 (7H, m). 362 —H —NHCONHPh ¹H NMR 3.55 (2H, s), 6.76 (1H, d, J = 8.6 Hz), 6.89 (1H, s), 6.95-7.02 (3H, m), 7.03-7.12 (2H, m), 7.21-7.36 (6H, m), 6.68 (1H, d, J = 2.9 Hz). 363 —H

¹H NMR 1.70-1.90 (4H, m), 2.18 (2H, brs), 2.40- 2.50 (2H, m), 3.13-3.29 (2H, m), 4.56 (2H, s), 6.76 (1H, d, J = 8.6 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.09 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.72 (1H, d, J = 3.0 Hz). 364 —H —CH(CH₃)COOCH₃ MS 272 (M⁺) 365 —H —C(CH₃)₂COOCH₃ MS 286 (M⁺) 366 —H

¹H NMR 1.50 (9H, s), 3.55 (2H, brs), 3.72 (2H, m), 3.78 (2H, m), 4.25 (2H, s), 6.80 (1H, d, J = 8.6 Hz), 7.08 (2H, d, J = 8.9 Hz), 7.10 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.24 (2H, d, J = 8.9 Hz), 7.72 (1H, d, J = 3.0 Hz). 367 —H

¹H NMR 1.48 (9H, s), 3.07 (4H, brs), 3.47 (2H, brs), 3.57 (4H, t, J = 5.0 Hz), 6.72 (1H, d, J = 8.5 Hz), 6.92 (2H, d, J = 9.0 Hz), 7.00 (2H, d, J = 9.0 Hz), 7.06 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.70 (1H, d, J = 3.0 Hz). 368 —H

¹H NMR 1.27 (3H, t, J = 7.0 Hz), 1.44 (2H, dq, J = 4.0 Hz, 12.5 Hz), 1.83 (2H, brd, J = 13.0 Hz), 1.91 (1H, m), 2.28 (2H, d, J = 7.0 Hz), 2.70 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.46 (2H, brs), 3.57 (2H, brd, J = 12.0 Hz), 4.15 (2H, q, J = 7.0 Hz), 6.69 (1H, d, J = 8.5 Hz), 6.92 (2H, d, J = 9.0 Hz), 6.97 (2H, d, J = 9.0 Hz), 7.05 (2H, dd, J = 8.5 Hz, 3.0 Hz), 7.70 (1H, d, J = 3.0 Hz). 369 —CH₃

¹H NMR 1.27 (3H, t, J = 7.1 Hz), 1.86-2.05 (4H, m), 2.14 (3H, s), 2.35-2.44 (1H, m), 2.69-2.79 (2H, m), 3.43 (2H, brs), 3.55-3.59 (2H, m), 4.16 (2H, q, J = 7.1 Hz), 6.62 (1H, d, J = 8.6 Hz), 6.74-6.82 (2H, m), 6.89 (1H, d, J = 8.6 Hz), 7.03 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.68 (1H, d, J = 3.0 Hz). 370 —OCH₃

¹H NMR 1.27 (3H, t, J = 7.1 Hz), 1.38-1.50 (2H, m), 1.87-2.06 (3H, m), 2.29 (2H, d, J = 7.1 Hz), 2.69- 2.77 (2H, m), 3.42 (2H, brs), 3.58 (2H, d, J = 12.2 Hz), 3.75 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 6.49 (1H, dd, J = 8.6 Hz, 2.6 Hz), 6.59 (1H, d, J = 2.6 Hz), 6.70 (1H, d, J = 8.6 Hz), 6.96 (1H, d, J = 8.6 Hz), 7.04 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.65 (1H, d, J = 3.0 Hz). 371 —CH₃

¹H NMR 1.27 (3H, t, J = 7.1 Hz), 1.37-1.49 (2H, m), 1.80-2.04 (3H, m), 2.13 (3H, s), 2.28 (2H, d, J = 6.9 Hz), 2.69 (2H, dd, J = 12.0 Hz, 9.9 Hz), 3.41- 3.59 (4H, m), 4.15 (2H, q, J = 7.3 Hz), 6.60 (1H, d, J = 8.6 Hz), 6.73-6.81 (2H, m), 6.88 (1H, d, J = 8.6 Hz), 7.02 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.66 (1H, d, J = 2.8 Hz).

TABLE 53

Reference Example No. R₂₁₃ ¹H NMR (CDCl₃) δ ppm 372

3.51 (2H, brs), 3.94-4.12 (4H, m), 5.78 (1H, s), 6.73 (1H, d, J = 8.6 Hz), 6.99-7.09 (3H, m), 7.43 (2H, d, J = 8.5 Hz), 7.70 (1H, d, J = 2.7 Hz). 373

0.05 (6H, s), 0.91 (9H, s), 1.77-1.88 (2H, m), 2.62- 2.68 (2H, m), 3.62-3.66 (2H, m), 6.73 (1H, d, J = 8.9 Hz), 6.95-7.17 (5H, m), 7.72 (1H, d, J = 3.0 Hz). 374

−0.07 (6H, s), 0.81 (9H, s), 2.73 (2H, t, J = 7.3 Hz), 3.72 (2H, t, J = 7.3 Hz), 6.66 (1H, dd, J = 8.6 Hz, 0.7 Hz), 6.88-6.92 (2H, m), 6.99 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.10 (2H, d, J = 8.6 Hz), 7.64 (1H, d, J = 3.0 Hz). 375 morpholino 3.09-3.13 (4H, m), 3.84-3.87 (4H, m), 6.71 (1H, d, J = 8.6 Hz), 6.90 (2H, d, J = 8.9 Hz), 7.02 (2H, d, J = 9.2 Hz), 7.05 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.69 (1H, d, J =3.0 Hz) 376

3.12 (1H, dd, J = 14.2 Hz, 9.8 Hz), 3.52 (1H, dd, J = 14.2 Hz, 3.8 Hz), 3.70 (2H, s), 4.51 (1H, dd, J = 9.8 Hz, 3.8 Hz), 6.78 (1H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.6 Hz), 7.09 (1H, dd, J = 8.6 Hz, 3.1 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.71 (1H, d, J = 3.1 Hz), 7.98 (1H, brs). 377 —CH═C(COOCH₃)₂ 3.84 (3H, s), 3.85 (3H, s), 6.82 (1H, d, J = 8.3 Hz), 7.03 (2H, d, J = 8.9 Hz), 7.02-7.10 (1H, m), 7.42 (2H, d, J = 8.9 Hz), 7.70-7.76 (2H, m). 378

1.27 (3H, t, J = 7.0 Hz), 1.88 (2H, m), 2.02 (2H, m), 2.40 (1H, m), 2.75 (2H, dt, J = 3.0 Hz, 12.0 Hz), 3.46 (2H, brs), 3.56 (2H, dt, J = 13.0 Hz, 3.0 Hz), 4.15 (2H, q, J = 7.0 Hz), 6.70 (1H, d, J = 8.5 Hz), 6.92 (2H, d, J = 9.0 Hz), 6.98 (2H, d, J = 9.0 Hz), 7.05 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.70 (1H, d, J = 3.0 Hz). 379

1.28 (3H, t, J = 7.0 Hz), 1.66-1.72 (2H, m), 1.82 (1H, m), 2.01 (1H, m), 2.68 (1H, m), 2.78 (1H, m), 2.99 (1H, dd, J = 12.0 Hz, 10.0 Hz), 3.39 (1H, brd, J = 12.0 Hz), 3.47 (2H, brs), 3.62 (1H, dd, J = 12.0 Hz, 4.0 Hz), 4.17 (2H, q, J = 7.0 Hz), 6.70 (1H, d, J = 8.5 Hz), 6.94 (2H, d, J = 9.0 Hz), 6.93 (2H, d, J = 9.0 Hz), 7.06 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.70 (1H, d, J = 3.0 Hz). 380 —CH(CH₃)CH₂COOC₂H₅ 1.18 (3H, t, J = 7.2 Hz), 1.27 (3H, d, J = 7.0 Hz), 2.43- 2.60 (2H, m), 3.19-3.29 (1H, m), 3.48 (2H, brs), 4.06 (2H, q, J = 7.2 Hz), 6.72 (1H, d, J = 8.7 Hz), 6.96 (2H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.70 (1H, d, J = 3.0 Hz).

TABLE 54

Reference Example No. R₂₁₄ ¹H NMR (CDCl₃) δ ppm or MS 381

MS 460 (M⁺) 382

¹H NMR 1.90-2.03 (1H, m), 2.20- 2.55 (3H, m), 3.11-3.25 (1H, m), 3.25- 3.38 (1H, m), 3.43 (2H, s), 3.57 (2H, s), 3.60-3.88 (2H, m), 4.70 (1H, d, J = 6.5 Hz), 5.18 (1H, d, J = 6.5 Hz), 6.76 (1H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.5 Hz), 7.08 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.20- 7.35 (7H, m), 7.73 (1H, dd, J = 3.1 Hz, 0.5 Hz). 383

¹H NMR 2.25 (4H, t, J = 5.0 Hz), 3.19 (3H, s), 3.22 (4H, t, J = 5.0 Hz), 3.43 (2H, s), 3.56 (2H, brs), 6.77 (1H, d, J = 8.6 Hz), 7.00 (2H, d, J = 9.2 Hz), 7.05 (2H, d, J = 9.2 Hz), 7.09 (1H, dd, J = 8.6 Hz, 2.8 Hz), 7.17-7.35 (5H, m), 7.72 (1H, d, J = 2.8 Hz). 384

¹H NMR 2.20 (3H, s), 3.07 (1H, dd, J = 14.2 Hz, 10.1 Hz), 3.50 (2H, brs), 3.52 (1H, dd, J = 14.2 Hz, 3.8 Hz), 4.51 (1H, dd, J = 10.1 Hz, 3.8 Hz), 6.73 (1H, d, J = 8.5 Hz), 6.90 (1H, d, J = 8.5 Hz), 7.03 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.08 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.10 (1H, d, J = 3.0 Hz), 7.67 (1H, d, J = 3.0 Hz), 8.10 (1H, brs). 385

¹H NMR 3.62 (2H, brs), 3.97 (3H, s), 6.86 (1H, d, J = 8.6 Hz), 7.12 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.32 (1H, dd, J = 8.9 Hz, 2.5 Hz), 7.41 (1H, d, J = 2.1 Hz), 7.72-7.75 (2H, m), 7.92 (1H, d, J = 8.9 Hz), 8.02 (1H, dd, J = 8.6 Hz, 1.7 Hz), 8.56 (1H, s). 386

¹H NMR 3.63 (2H, brs), 3.98 (3H, s), 6.90 (1H, d, J = 8.6 Hz), 6.94 (1H, d, J = 8.2 Hz), 7.15 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.54-7.57 (1H, m), 7.62-7.68 (1H, m), 7.77 (1H, d, J = 3.0 Hz), 8.18 (1H, d, J = 8.2 Hz), 8.32-8.35 (1H, m), 9.03 (1H, d, J = 8.7 Hz). 387

¹H NMR 1.45 (3H, t, J = 7.1 Hz), 3.57 (2H, brs), 4.47 (2H, q, J = 7.1 Hz), 6.83 (1H, d, J = 8.6 Hz), 7.12 (1H, dd, J = 8.6 Hz, 3.1 Hz), 7.38 (1H, dd, J = 9.4 Hz, 2.6 Hz), 7.43-7.49 (2H, m), 7.75 (1H, d, J = 3.0 Hz), 7.89 (1H, d, J = 8.2 Hz), 8.10 (1H, dd, J = 7.3 Hz, 1.3 Hz), 8.93 (1H, d, J = 9.4 Hz).

TABLE 55

Reference Example No. R₂₁₅ R₂₁₆ R₂₁₇ Xa₉ Xa₁₀ ¹H NMR (CDCl₃) δ ppm or MS 388 —H —CH₃ piperonyl —CH₂— —CH₂— MS 474 (M⁺) 389 —H —F benzyl none none ¹H NMR 2.46 (4H, brs), 3.54 (6H, brs), 6.83 (1H, d, J = 8.7 Hz), 7.09 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.16-7.36 (8H, m), 7.61 (1H, d, J = 3.0 Hz). 390 —H —OCH₃ piperonyl —CH₂— —CH₂— ¹H NMR 2.31-2.41 (4H, m), 2.59-2.65 (2H, m), 2.92- 2.98 (2H, m), 3.41 (4H, brs), 3.62-3.65 (2H, m), 3.76 (3H, s), 5.95 (2H, s), 6.71-6.79 (4H, m), 6.83-6.85 (2H, m), 6.97 (1H, d, J = 8.1 Hz), 7.06 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.63 (1H, d, J = 2.8 Hz). 391 —H —H —COOC(CH₃)₃ —CH₂— —CH(OH)— ¹H NMR 1.47 (9H, s), 2.81- 2.98 (2H, m), 3.01-3.20 (1H, m), 3.29 (3H, brs), 3.39 (2H, brs), 3.51 (2H, brs), 3.58- 3.78 (3H, m), 4.58 (1H, q, J = 7.0 Hz), 6.75 (1H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.6 Hz), 7.07 (1H, dd, J = 8.8 Hz, 3.0 Hz), 7.19 (2H, d, J = 8.6 Hz), 7.67 (1H, d, J = 3.0 Hz). 392 —CH₃ —H piperonyl —CH₂— —CH₂— MS 474 (M ⁺)

TABLE 56

Reference Example No. R₂₁₈ R₂₁₉ R₂₂₀ ¹H NMR (CDCl₃) δ ppm or MS 393 —H —H —H ¹H NMR 2.42-2.49 (4H, m), 3.42-3.48 (4H, m), 3.66-3.72 (2H, m), 3.86 (2H, d, J = 4.3 Hz), 4.82 (1H, t, J = 4.3 Hz), 5.96 (2H, s), 6.62 (2H, d, J = 8.8 Hz), 6.68 (1H, d, J = 8.6 Hz), 6.73-6.78 (2H, m), 6.86 (1H, d, J = 1.0 Hz), 6.95 (1H, d, J = 8.8 Hz), 7.05 (1H, dd, J = 3.0 Hz, 8.6 Hz), 7.69 (1H, d, J = 3.0 Hz) 394 —H —H —Ac ¹H NMR 1.94 (3H, s), 2.45-2.55 (4H, m), 3.45-3.70 (8H, m), 4.42 (2H, s), 5.95 (2H, s), 6.75-6.85 (3H, m), 6.92 (1H, s), 7.04 (2H, d, J = 8.8 Hz), 7.12 (1H, dd, J = 3.0 Hz, 8.6 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.72 (1H, d, J = 3.0 Hz). 395 —H —H —COC₂H₅ ¹H NMR 1.06 (3H, t, J = 7.5 Hz), 2.17 (2H, q, J = 7.5 Hz), 2.40-2.45 (4H, m), 3.41 (4H, s), 3.59 (2H, s), 4.42 (2H, s), 5.94 (2H, s), 6.70-6.75 (2H, m), 6.80-6.85 (2H, m), 7.04 (2H, d, J = 8.7 Hz), 7.11 (1H, dd, J = 3.1 Hz, 8.6 Hz), 7.36 (2H, d, J = 8.7 Hz), 7.72 (1H, d, J = 3.1 Hz). 396 —H —H

¹H NMR 0.60-1.55 (5H, m), 2.39 (4H, brs), 3.42 (4H, brs), 3.55 (2H, brs), 4.46 (2H, brs), 5.94 (2H, s), 6.69-6.75 (2H, m), 6.77- 6.85 (2H, m), 7.00-7.15 (2H, m), 7.40- 7.46 (2H, m), 7.72 (1H, s). 397 —H —H cyclopropyl ¹H NMR 0.60-0.66 (2H, m), 0.77-0.83 (2H, m), 2.42-2.44 (4H, m), 2.77-2.79 (1H, m), 3.43-3.52 (6H, m), 3.59-3.62 (2H, m), 4.16 (2H, s), 5.95 (2H, s), 6.66 (1H, d, J = 8.6 Hz), 6.75 (2H, s), 6.86-6.97 (5H, m), 7.03 (1H, dd, J = 8.6 Hz, 2.8 Hz), 7.70 (1H, d, J = 2.8 Hz). 398 —CH₃ —CH₃ —C₂H₅ MS 517 (M⁺) 399 —COOCH₃ —H —C₂H₅ MS 547 (M⁺)

TABLE 57

Reference Example No. Xa₁₁ M ¹H NMR (CDCl₃) δ ppm 400 —NH— 0 2.40-2.50 (4H, m), 3.40-3.55 (6H, m), 3.68 (2H, brs), 5.95 (2H, s), 6.27 (1H, s), 6.30-6.55 (2H, m), 6.65-6.95 (5H, m), 7.20-7.30 (2H, m). 401 —NH— 1 2.40-2.50 (4H, m), 3.35-3.45 (4H, m), 3.55-3.70 (4H, m), 3.83 (2H, d, J = 4.4 Hz), 4.72 (1H, t, J = 4.4 Hz), 5.95 (2H, s), 6.30-6.40 (1H, m), 6.45-6.60 (3H, m). 402 —N(Ac)— 1 1.91 (3H, s), 2.40-2.50 (4H, m), 3.45-3.75 (8H, m), 4.41 (2H, s), 5.94 (2H, s), 6.40-6.52 (2H, m), 6.70-6.75 (2H, m), 6.80- 6.95 (4H, m), 7.28 (2H, d, J = 9.0 Hz). 403 —O— 1 2.41 (4H, brs), 3.42 (2H, s), 3.50-3.80 (6H, m), 4.63 (2H, s), 5.94 (2H, s), 6.40 (1H, ddd, J = 1.2 Hz, 2.6 Hz, 7.4 Hz), 6.50 (1H, dd, J = 2.6 Hz, 12.1 Hz), 6.65-6.75 (2H, m), 6.80- 6.95 (6H, m).

Reference Example 404 Production of methyl 3-[(4-hydroxyphenyl)methylamino]-propionate

Methyl 3-[(4-benzyloxyphenyl)methylamino]-propionate (27.3 g, 91.1 mmol) was dissolved in ethanol (300 mL), and the resulting solution was cooled with ice and 10% palladium-carbon (3.0 g) was added. The resulting solution was stirred for 4.5 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered through Celite to remove insoluble matter, and the filtrate was concentrated under reduced pressure to thereby yield 19.1 g of the title compound.

Appearance: Red oil

¹H NMR (CDCl₃) δ 2.51-2.56 (2H, m), 2.83 (3H, brs), 3.57 (2H, brs), 3.66 (3H, s), 4.99 (1H, brs), 6.71-6.74 (4H, m).

The following compounds were produced in the same manner as in Reference Example 404.

Reference Example 405 Ethyl [acetyl(4-hydroxyphenyl)amino]acetate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7.1 Hz), 1.92 (3H, s), 4.19 (2H, q, J=7.1 Hz), 4.34 (2H, s), 6.16 (1H, s), 6.87 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8 Hz).

TABLE 58 Reference Example No. Chemical Structure mp (° C.) or ¹H NMR (CDCl₃) δ ppm 406

mp 172.0-173.0 407

¹H NMR 2.24 (3H, s), 3.25-3.39 (2H, m), 3.66-3.81 (2H, m), 4.36 (2H, s), 4.93 (1H, s), 5.95 (2H, s), 6.71 (1H, d, J = 8.6 Hz), 6.77 (2H, d, J = 0.6 Hz), 6.83 (1H, s), 7.15 (1H, dd, J = 2.8 Hz, 8.6 Hz), 7.32 (1H, d, J = 2.8 Hz). 408

¹H NMR 1.94-2.12 (2H, m), 2.08 (3H, s), 3.29 (2H, t, J = 6.0 Hz), 3.58 (2H, t, J = 6.0 Hz), 3.89 (3H, s), 3.93 (3H, s), 4.57 (2H, s), 6.34 (1H, d, J = 8.4 Hz), 6.71 (1H, dd, J = 2.6 Hz, 8.4 Hz), 6.75-6.93 (3H, m), 6.96 (1H, d, J = 1.3 Hz), 7.61 (1H, s). 409

¹H NMR 2.07 (3H, s), 2.09-2.18 (2H, m), 2.37-2.50 (4H, m), 3.41 (2H, s), 3.43-3.54 (4H, m), 3.54-3.68 (4H, m), 4.22 (2H, s), 5.94 (2H, s), 6.35 (1H, d, J = 8.4 Hz), 6.62- 6.77 (3H, m), 6.83 (1H, d, J = 1.1 Hz), 6.88 (1H, d, J = 2.4 Hz). 410

¹H NMR 1.49 (9H, s), 2.07 (3H, s), 2.07-2.21 (2H, m), 3.45 (2H, t, J = 5.9 Hz), 3.61 (2H, t, J = 5.9 Hz), 4.07 (2H, s), 6.33 (1H, d, J = 8.4 Hz), 6.71 (1H, dd, J = 2.6 Hz, 8.4 Hz), 6.87 (1H, d, J = 2.6 Hz), 7.26 (1H, s).

Reference Example 411 Production of [4-(5-aminopyridin-2-yloxy)phenyl](4-piperonylpiperazin-1-yl)methanone

[4-(5-nitropyridin-2-yloxy)phenyl] (4-piperonylpiperazin-1-yl)methanone (0.36 g, 0.78 mmol) was dissolved in a mixed solvent consisting of ethanol (5 mL) and THF (5 mL). To the resulting solution was added 5% platinum-carbon (0.06 g), and stirred at room temperature under a hydrogen atmosphere. Two hours later, the 5% platinum-carbon was removed by filtration, and the solvent was evaporated under reduced pressure, to thereby yield 0.32 g of the title compound.

Appearance: Pale yellow amorphous powder

¹H NMR (CDCl₃) δ 2.43 (4H, brs), 3.44 (2H, s), 3.58 (6H, brs), 5.95 (2H, s), 6.74 (2H, s), 6.80 (1H, d, J=8.6 Hz), 6.85 (1H, s), 7.05 (2H, d, J=8.6 Hz), 7.10 (1H, dd, J=8.6 Hz, 3.0 Hz), 7.40 (2H, d, J=8.7 Hz), 7.74 (1H, d, J=2.6 Hz).

The following compounds were produced in the same manner as in Reference Example 411.

Reference Example 412 4-[5-(4-Trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenylamine

¹H NMR (CDCl₃) δ 3.63 (2H, brs), 5.02 (2H, s), 6.70 (2H, d, J=8.9 Hz), 6.88 (1H, d, J=8.4 Hz), 6.94 (2H, d, J=8.9 Hz), 7.01 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.4 Hz), 7.72 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.22 (1H, d, J=2.3 z).

Reference Example 413 3-Methyl-4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenylamine

¹H NMR (CDCl₃) δ 2.08 (3H, s), 3.58 (2H, brs), 5.02 (2H, s), 6.65 (1H, dd, J=8.2 Hz, 2.8 Hz), 6.60 (1H, d, J=2.8 Hz), 6.83-6.87 (2H, m), 7.02 (2H, d, J=8.9 Hz), 7.56 (2H, d, J=9.1 Hz), 7.72 (1H, dd, J=8.6 Hz, 2.5 Hz), 8.21 (1H, d, J=2.5 Hz).

Reference Example 414 2-{[4-(4-Aminophenoxy)phenyl]methylamino}-1-(4-piperonylppiperazin-1-yl)ethanone

¹H NMR (CDCl₃) δ 2.41 (4H, t, J=5.1 Hz), 2.99 (3H, s), 3.42 (2H, s), 3.48 (2H, t, J=4.8 Hz), 3.50 (2H, brs), 3.62 (2H, t, J=4.8 Hz), 4.04 (2H, s), 5.95 (2H, s), 6.61-6.68 (4H, m), 6.73-6.88 (7H, m).

Reference Example 415 2-{[3-(5-Aminopyridin-2-yloxy)phenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone

¹H NMR (CDCl₃) δ 2.40 (4H, t, J=4.9 Hz), 3.00 (3H, s), 3.41 (2H, s), 3.44-3.46 (2H, m), 3.51 (2H, brs), 3.59-3.61 (2H, m), 4.06 (2H, s), 5.95 (2H, s), 6.35-6.45 (3H, m), 6.70-6.74 (3H, m), 6.85 (1H, s), 7.05 (1H, dd, J=8.6 Hz, 3.1 Hz), 7.12-7.18 (1H, m), 7.73 (1H, d, J=3.1 Hz).

TABLE 59

Reference Example No. R₂₂₁ R₂₂₂ R₂₂₃ R₂₂₄ R₂₂₅ ¹H NMR (CDCl₃) δ ppm or MS 416 —H —H —CH₃ —CH₃ —CH₃ ¹H NMR 1.25 (3H, t, J = 7.1 Hz), 1.38 (6H, s), 2.86 (3H, s), 3.50 (2H, brs), 4.17 (2H, q, J = 7.1 Hz), 6.73 (1H, dd, J = 8.6 Hz, 0.3 Hz), 6.93 (2H, d, J = 9.1 Hz), 7.02- 7.09 (3H, m), 7.73 (1H, d, J = 3.0 Hz). 417 —F —H —CH₃ —H —H ¹H NMR 1.26 (3H, t, J = 7.1 Hz), 3.05 (3H, s), 3.44 (2H, brs), 4.02 (2H, s), 4.19 (2H, q, J = 7.1 Hz), 6.38- 6.51 (2H, m), 6.75 (1H, d, J = 8.6 Hz), 7.01-7.13 (2H, m), 7.63 (1H, d, J = 3.0 Hz). 418 —F —H —C₂H₅ —H —H ¹H NMR 1.16-1.30 (6H, m), 3.43 (2H, brs), 3.43 (2H, q, J = 7.1 Hz), 3.98 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 6.33-6.47 (2H, m), 6.75 (1H, d, J = 8.6 Hz), 6.99-7.09 (2H, m), 7.64 (1H, d, J = 3.0 Hz). 419 —F —H —(CH₂)₂CH₃ —H —H ¹H NMR 0.95 (3H, t, J = 7.4 Hz), 1.27 (3H, t, J = 7.3 Hz), 1.59- 1.70 (2H, m), 3.31 (2H, t, J = 7.6 z), 3.45 (2H, brs), 3.99 (2H, s), 4.20 (2H, q, J = 7.1 Hz), 6.32-6.45 (2H, m), 6.75 (1H, dd, J = 8.7 Hz, 0.7 Hz), 7.04 (1H, t, J = 9.1 Hz), 7.05 (1H, dd, J = 7.4 Hz, 5.8 Hz), 7.64 (1H, dd, J = 3.0 Hz, 0.7 Hz). 420 —F —H —Ac —H —H ¹H NMR 1.29 (3H, t, J = 7.1 Hz), 1.98 (3H, s), 3.55 (2H, brs), 4.21 (2H, q, J = 7.1 Hz), 4.35 (2H, s), 6.87 (1H, d, J = 8.7 Hz), 7.10-7.29 (4H, m), 7.63 (1H, d, J = 3.0 Hz). 421 —H —CF3 —C₂H₅ —H —H MS 383 (M⁺)

TABLE 60

Reference Example No. Xa₁₂ R₂₂₆ ¹H NMR (CDCl₃) δ ppm 422 —O— —CH₂CN 3.54 (2H, brs), 3.72 (2H, s), 6.79 (1H, d, J = 8.5 Hz), 7.06 (2H, d, J = 8.9 Hz), 7.09 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.30 (2H, d, J = 8.9 Hz), 7.71 (1H, d, J = 3.0 Hz). 423 —O—

2.41 (4H, t, J = 5.1 Hz), 3.38 (4H, t, J = 5.1 Hz), 3.42 (2H, s), 3.54 (2H, brs), 4.37 (2H, d, J = 5.1 Hz), 4.72 (1H, t, J = 5.1 Hz), 5.94 (2H, s), 6.74 (2H, s), 6.77 (1H, d, J = 8.7 Hz), 6.85 (1H, s), 7.01 (2H, d, J = 8.5 Hz), 7.08 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.28 (2H, d, J = 8.5 Hz), 7.68 (1H, d, J = 2.8 Hz). 424 —O—

2.45-2.47 (4H, m), 2.73-2.98 (2H, m), 3.45 (2H, s), 3.49-3.72 (7H, m), 3.85- 3.91 (1H, m), 4.24-4.30 (1H, m), 5.96 (2H, s), 6.74-6.78 (3H, m), 6.86 (1H, s), 7.05-7.11 (3H, m), 7.53- 7.58 (2H, m), 7.70 (1H, d, J = 3.0 Hz). 425 —O—

1.35 (3H, d, J = 6.6 Hz), 2.37-2.52 (4H, m), 3.31 (1H, q, J = 6.6 Hz), 3.67- 3.72 (4H, m), 6.76 (1H, d, J = 8.6 Hz), 6.99 (2H, d, J = 8.3 Hz), 7.08 (1H, dd, J = 8.6 Hz, 2.3 Hz), 7.27 (2H, d, J = 8.4 Hz), 7.72 (1H, d, J = 3.0 Hz). 426 —N(CH₃)—

1.30 (3H, t, J = 7.1 Hz), 2.76 (4H, t, J = 5.0 Hz), 3.24 (4H, t, J = 5.0 Hz), 3.28 (3H, s), 3.35 (4H, s), 4.21 (2H, q, J = 7.1 Hz), 6.42 (1H, dd, J = 8.8 Hz, 0.7 Hz), 6.83 (1H, dd, J = 8.8 Hz, 2.9 Hz), 6.92 (2H, d, J = 8.9 Hz), 7.10 (2H, d, J = 8.9 Hz), 7.79 (1H, dd, J = 2.9 Hz, 0.7 Hz). 427 —N(CH₃)—

1.28 (3H, t, J = 7.1 Hz), 1.46 (2H, qd, J = 12.3 Hz, 3.6 Hz), 1.77-2.10 (3H, m), 2.29 (2H, d, J = 6.9 Hz), 2.73 (2H, td, J = 12.3 Hz, 2.4 Hz), 3.23 (2H, brs), 3.35 (3H, s), 3.63 (2H, d, J = 12.3 Hz), 4.15 (2H, q, J = 7.1 Hz), 6.41 (1H, d, J = 8.9 Hz), 6.82 (1H, dd, J = 8.9 Hz, 3.0 Hz), 6.92 (2H, d, J = 8.9 Hz), 7.09 (2H, d, J = 8.9 Hz), 7.79 (1H, d, J = 2.5 Hz). 428 —O—

3.28-3.42 (2H, m), 3.43-3.59 (2H, m), 3.71-3.88 (2H, m), 4.47 (2H, s), 6.73 (1H, d, J = 8.6 Hz), 7.01-7.11 (3H, m), 7.25-7.39 (5H, m), 7.51-7.59 (2H, m), 7.70 (1H, d, J = 2.9 Hz).

TABLE 61

Reference Example No. R₂₂₇ R₂₂₈ ¹H NMR (CDCl₃) δ ppm or MS 429 —F

MS 478 (M⁺) 430 —CH₃

¹H NMR 1.96-2.11 (2H, m), 2.19 (3H, s), 3.29 (2H, t, J = 5.9 Hz), 3.46 (2H, s), 3.68 (2H, t, J = 5.9 Hz), 4.52 (2H, s), 5.95 (2H, s), 6.67 (1H, d, J = 8.6 Hz), 6.73-6.81 (2H, m), 6.88 (1H, s), 6.93 (1H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 3.0 Hz, 8.6 Hz), 7.09 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.18-7.22 (1H, m), 7.00 (1H, d, J = 3.0 Hz). 431 —CH₃

¹H NMR 1.99-2.11 (2H, m), 2.19 (3H, s), 3.29 (2H, t, J = 6.0 Hz), 3.47 (2H, s), 3.68 (2H, d, J = 6.0 Hz), 3.88 (3H, s), 3.88 (3H, s), 4.56 (2H, s), 6.68 (1H, d, J = 8.6 Hz), 6.82 (1H, d, J = 8.1 Hz), 6.86 (1H, dd, J = 1.8 Hz, 8.1 Hz), 6.91 (1H, d, J = 1.8 Hz), 6.93 (1H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 3.0 Hz, 8.6 Hz), 7.09 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.19 (1H, d, J = 2.6 Hz), 7.69 (1H, d, J = 3.0 Hz). 432 —CH₃

¹H NMR 2.10-2.21 (2H, m), 2.35-2.48 (4H, m), 3.42 (2H, s), 3.43-3.54 (6H, m), 3.57-3.66 (2H, m), 3.73 (2H, t, J = 5.7 Hz), 4.21 (2H, s), 5.95 (2H, s), 6.66 (1H, d, J = 8.6 Hz), 6.69-6.77 (2H, m), 6.84 (1H, d, J = 1.2 Hz), 6.92 (1H, d, J = 8.6 Hz), 7.02-7.09 (2H, m), 7.17 (1H, d, J = 2.4 Hz), 7.69 (1H, d, J = 2.8 Hz). 433 —CH₃

¹H NMR 1.38 (3H, t, J = 7.1 Hz), 2.19 (3H, s), 2.19-2.33 (2H, m), 3.47 (2H, s), 3.73-3.93 (4H, m), 4.36 (2H, q, J = 7.1 Hz), 6.67 (1H, d, J = 8.6 Hz), 6.94 (1H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 3.0 Hz, 8.6 Hz), 7.12 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.22 (1H, d, J = 2.6 Hz), 7.40- 7.48 (2H, m), 7.69 (1H, d, J = 3.0 Hz), 7.95-8.04 (2H, m). 434 —CH₃

¹H NMR 1.47 (9H, s), 2.05-2.24 (5H, m), 3.34-3.54 (4H, m), 3.77 (2H, t, J = 5.8 Hz), 4.04 (2H, s), 6.65 (1H, d, J = 8.6 Hz), 6.90 (1H, d, J = 8.6 Hz), 6.99- 7.10 (2H, m), 7.17 (1H, d, J = 2.4 Hz), 7.68 (1H, d, J = 3.0 Hz).

TABLE 62

Reference Example No. R₂₂₉ Xa₁₃ R₂₃₀ Xa₁₄ ¹H NMR (CDCl₃) δ ppm 435 —H —CO— 3-pyridyl —CH₂— 3.23 (4H, brs), 3.62 (2H, brs), 3.81 (4H, brs), 6.83 (1H, d, J = 8.6 Hz), 7.09 (2H, d, J = 8.6 Hz), 7.12 (1H, dd, J = 8.6 Hz, 3.1 Hz), 7.20-7.21 (2H, m), 7.45 (2H, d, J = 8.7 Hz), 7.55 (1H, d, J = 3.0 Hz), 8.14-8.17 (1H, m), 8.31-8.33 (1H, m). 436 —H none piperonyl —CO— 3.37 (4H, s), 3.48 (2H, brs), 3.90 (2H, s), 4.57 (2H, s), 5.95 (2H, s), 6.72 (1H, dd, J = 8.5 Hz, 0.7 Hz), 6.74- 6.78 (2H, m), 6.78-6.82 (1H, m), 6.86 (2H, d, J = 9.1 Hz), 7.02 (2H, d, J = 9.1 Hz), 7.06 (1H, dd, J = 8.5 Hz, 2.9 Hz), 7.69 (1H, d, J = 2.9 Hz). 437 —COOCH₃ none benzyl —CH₂— 2.58-2.62 (4H, m), 3.14-3.18 (4H, m), 3.61 (2H, s), 3.65 (3H, s), 6.63 (1H, d, J = 8.7 Hz), 6.95 (1H, d, J = 8.9 Hz), 7.12-7.18 (2H, m), 7.25-7.36 (5H, m), 7.41 (1H, d, J = 3.0 Hz), 7.51 (1H, d, J = 2.8 Hz). 438 —H —CH₂— —COOC(CH₃)₃ —CH₂— 1.45 (9H, s), 2.36-2.40 (4H, m), 3.40- 3.44 (4H, m), 3.47 (2H, s), 3.56 (2H, brs), 6.76 (1H, d, J = 8.6 Hz), 6.97- 7.02 (2H, m), 7.08 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.25-7.29 (2H, m), 7.71 (1H, d, J = 3.0 Hz). 439 —H —CO— benzyl —CH₂— 2.38 (4H, brs), 3.33 (2H, brs), 3.50 (4H, brs), 5.17 (2H, brs), 6.82 (1H, d, J = 8.6 Hz), 6.96 (2H, d, J = 8.7 Hz), 7.10 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.27-7.33 (5H, m), 7.36 (2H, d, J = 8.7 Hz), 7.57 (1H, d, J = 3.0 Hz). 440 —H —CO— 4-CH₃OPhCH₂— —CH₂— 2.44 (4H, brs), 3.48 (2H, s), 3.59 (4H, brs), 3.81 (3H, s), 6.80 (1H, dd, J = 8.6 Hz, 0.7 Hz), 6.85-6.89 (2H, m), 7.03-7.08 (2H, m), 7.11 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.21-7.26 (2H, m), 7.38-7.43 (2H, m), 7.73-7.75 (1H, m). 441 —H —SO₂— benzyl —CH₂— 2.42-2.57 (4H, m), 2.91-3.10 (4H, m), 3.47 (2H, s), 3.63 (2H, brs), 6.83 (1H, d, J = 8.6 Hz), 7.07-7.14 (3H, m), 7.18-7.31 (5H, m), 7.68 (2H, d, J = 8.8 Hz), 7.74 (1H, d, J = 2.0 Hz).

TABLE 63

Reference Example No. R₂₃₁ R₂₃₂ R₂₃₃ R₂₃₄ R₂₃₅ ¹H NMR (CDCl₃) δ ppm 442 —F —H —H —H —H 2.43-2.48 (4H, m), 3.44-3.47 (6H, m), 3.67- 3.68 (2H, m), 3.82 (2H, d, J = 4.1 Hz), 4.96 (1H, brs), 5.96 (2H, s), 6.36-6.43 (2H, m), 6.71-6.78 (3H, m), 6.86 (1H, brs), 6.97- 7.03 (1H, m), 7.06 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.63 (1H, d, J = 3.0 Hz). 443 —F —H —H —H —CH₃ 2.43-2.45 (4H, m), 3.01 (3H, s), 3.44 (2H, s), 3.47 (2H, brs), 3.63 (2H, brs), 4.07 (2H, s), 5.95 (2H, s), 6.39-6.50 (2H, m), 6.72-6.76 (3H, m), 6.85 (1H, s), 7.00-7.08 (2H, m), 7.63 (1H, dd, J = 3.0 Hz, 0.5 Hz). 444 —F —H —H —H —C₂H₅ 1.18 (3H, t, J = 7.1 Hz), 2.43 (4H, t, J = 5.0 Hz), 3.37-3.48 (8H, m), 3.63 (2H, brs), 4.01 (2H, s), 5.95 (2H, s), 6.35-6.46 (2H, m), 6.72-6.77 (3H, m), 6.85 (1H, s), 6.99 (1H, d, J = 8.9 Hz), 7.05 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.63 (1H, d, J = 3.0 Hz). 445 —F —H —H —F —CH₃ 2.33-2.49 (4H, m), 2.93 (3H, s), 3.38-3.68 (8H, m), 4.00 (2H, s), 5.95 (2H, s), 6.71-6.77 (2H, s), 6.78-6.82 (2H, m), 6.83-6.91 (2H, m), 7.08 (1H, dd, J = 2.9 Hz, 8.6 Hz), 7.62 (1H, d, J = 2.9 Hz). 446 —F —H —H —F —C₂H₅ 1.11 (3H, t, J = 7.1 Hz), 2.31-2.49 (4H, m), 3.29 (2H, q, J = 7.1 Hz), 3.41 (2H, s), 3.42- 3.69 (6H, m), 3.96 (2H, s), 6.70-6.78 (2H, m), 6.79-6.91 (4H, m), 7.08 (1H, dd, J = 2.9 Hz, 8.6 Hz), 7.62 (1H, d, J = 2.9 Hz). 447 —F —H —F —H —CH₃ 2.36-2.52 (4H, m), 3.01 (3H, s), 3.34-3.54 (6H, m), 3.55-3.71 (2H, m), 4.05 (2H, s), 5.95 (2H, s), 6.18-6.29 (2H, m), 6.70-6.79 (2H, m), 6.82 (1H, d, J = 8.6 Hz), 6.85 (1H, d, J = 0.98 Hz), 7.07 (1H, dd, J = 2.9 Hz, 8.6 Hz), 7.59 (1H, d, J = 2.9 Hz). 448 —F —F —H —H —CH₃ 2.29-2.55 (4H, m), 2.95 (3H, s), 3.30-3.75 (8H, m), 4.01 (2H, s), 5.95 (2H, s), 6.60-6.95 (6H, m), 7.09 (1H, dd, J = 3.0 Hz, 8.6 Hz), 7.62 (1H, d, J = 3.0 Hz). 449 —CH₃ —CH₃ —H —H —CH₃ 2.11 (3H, s), 2.25 (3H, s), 2.36-2.42 (4H, m), 2.66 (3H, s), 3.41 (2H, s), 3.45 (2H, brs), 3.53- 3.56 (2H, m), 3.61-3.64 (2H, m), 3.73 (2H, s), 5.95 (2H, s), 6.67 (1H, d, J = 8.7 Hz), 6.70- 6.85 (4H, m), 6.95 (1H, d, J = 8.7 Hz), 7.03- 7.08 (1H, m), 7.67 (1H, d, J = 3.0 Hz). 450 —CH₃ —H —H —H

0.62-0.66 (2H, m), 0.76-0.83 (2H, m), 2.12 (3H, s), 2.40-2.46 (4H, m), 2.73-2.81 (1H, m), 3.43 (2H, s), 3.48-3.63 (4H, m), 4.15 (2H, s), 5.94 (2H, s), 6.58 (1H, d, J = 8.7 Hz), 6.68- 6.77 (4H, m), 6.87 (2H, d, J = 8.6 Hz), 7.01 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.67 (1H, d, J = 3.0 Hz).

TABLE 64

Reference Example No. R₂₃₆ R₂₃₇ R₂₃₈ Xa₁₅ ¹H NMR (CDCl₃) δ ppm or MS 451 —CH₃ —H —H —CO— ¹H NMR 2.20 (3H, s), 2.48-2.54 (4H, m), 3.44 (4H, s), 3.67-3.75 (2H, m), 4.23-4.27 (2H, m), 5.95 (2H, s), 6.63-6.78 (3H, m), 6.86 (1H, brs), 6.95 (1H, d, J = 8.7 Hz), 7.07 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.37 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.52 (1H, d, J = 2.5 Hz), 7.66 (1H, d, J = 3.0 Hz), 9.13 (1H, brs). 452 —CH₃ —H —CH₃ —CO— ¹H NMR 2.21-2.31 (7H, m), 3.28-3.40 (9H, m), 3.53 (2H, brs), 5.93 (2H, s), 6.66-6.80 (4H, m,) 6.91 (1H, d, J = 8.6 Hz), 7.03-7.12 (3H, m), 7.66 (1H, d, J = 3.0 Hz). 453 —H —H —SO₂CH₃ —CH₂— ¹H NMR 2.41 (4H, brs), 3.19 (3H, s), 3.34- 3.38 (2H, m), 3.42 (2H, s), 3.57-3.60 (4H, m), 4.51 (2H, s), 5.95 (2H, s), 6.70-6.77 (2H, m), 6.80 (1H, d, J = 8.6 Hz), 6.84 (1H, brs), 7.02 (2H, d, J = 8.7 Hz), 7.10 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.71 (1H, d, J = 3.0 Hz). 454 —CH₃ —H —SO₂CH₃ —CH₂— ¹H NMR 2.21 (3H, s), 2.41 (4H, brs), 3.20 (3H, s), 3.34-3.38 (2H, m), 3.42 (2H, s), 3.53 (2H, brs), 3.59-3.61 (2H, m), 4.51 (2H, s), 5.94 (2H, s), 6.70-6.77 (3H, m), 6.83 (1H, brs), 6.90 (1H, d, J = 8.6 Hz), 7.09 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.36 (1H, dd, J = 8.6 Hz, 2.1 Hz), 7.42 (1H, d, J = 2.3 Hz), 7.66 (1H, d, J = 3.0 Hz). 455 —CF₃ —H —C₂H₅ —CH₂— MS 557 (M⁺) 456 —CF₃ —H —CH₃ —CH₂— MS 543 (M⁺) 457 —CN —H —CH₃ —CH₂— MS 500 (M⁺) 458 —OCH₃ —H —SO₂CH₃ —CH₂— ¹H NMR 2.48 (4H, brs), 3.26 (3H, s), 3.42- 3.66 (8H, m), 3.82 (3H, s), 4.58 (2H, s), 5.99 (2H, s), 6.77-6.79 (2H, m), 6.81-6.88 (2H, m), 7.06-7.30 (4H, m), 7.67 (1H, d, J = 2.3 Hz). 459 —CH₃ —CH₃ —CH₃ —CH₂— MS 503 (M⁺)

TABLE 65

Reference Example No. R₂₃₉ R₂₄₀ R₂₄₁ ¹H NMR (CDCl₃) δ ppm 460 —H —CH₃ —H 2.40-2.44 (4H, m), 3.00 (3H, s), 3.49 (4H, brs), 3.63 (2H, brs), 4.05 (2H, s), 5.95 (2H, s), 6.67 (1H, d, J = 8.6 Hz), 6.69 (2H, d, J = 9.1 Hz), 6.74 (2H, brs), 6.85 (1H, brs), 6.97 (2H, d, J = 9.1 Hz), 7.03 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.68 (1H, d, J = 3.0 Hz). 461 —H —CH₃ —CH₃ 1.28 (3H, d, J = 6.6 Hz), 2.14-2.21 (1H, m), 2.28-2.35 (2H, m), 2.47-2.49 (1H, m), 2.75 (3H, s), 3.24-3.54 (3H, m), 3.38 (2H, s), 3.45 (2H, s), 3.78-3.84 (1H, m), 4.54 (1H, q, J = 6.8 Hz), 5.93 (2H, s), 6.68-6.75 (5H, m), 6.82 (1H, s), 6.99 (2H, d, J = 9.1 Hz), 7.05 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.69 (1H, dd, J = 3.1 Hz, 0.7 Hz). 462 —CH₃ —CH₃ —CH₃ 1.28 (3H, d, J = 6.6 Hz), 2.15 (3H, s), 2.15-2.21 (1H, m), 2.33- 2.36 (2H, m), 2.49 (1H, brs), 2.74 (3H, s), 3.25-3.55 (3H, m), 3.39 (2H, s), 3.42 (2H, s), 3.80 (1H, brs), 4.55 (1H, q, J = 6.4 Hz), 5.93 (2H, s), 6.55-6.59 (2H, m), 6.64 (1H, dd, J = 8.6 Hz, 0.5 Hz), 6.69-6.75 (2H, m), 6.83 (1H, brs), 6.90 (1H, d, J = 8.7 Hz), 7.04 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.67 (1H, dd, J = 3.0 Hz, 0.7 Hz). 463 —OCH₃ —CH₃ —H 2.31-2.50 (4H, m), 3.02 (3H, s), 3.31-3.57 (6H, m), 3.58- 3.70 (2H, m), 3.76 (3H, s), 4.06 (2H, s), 5.95 (2H, s), 6.24 (1H, dd, J = 8.7 Hz, 2.8 Hz), 6.37 (1H, d, J = 2.8 Hz), 6.68 (1H, d, J = 8.6 Hz), 6.69-6.79 (2H, m), 6.85 (1H, s), 6.94 (1H, d, J = 8.7 Hz), 7.02 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.65 (1H, d, J = 3.0 Hz). 464 —OCH₃ —C₂H₅ —H 1.18 (3H, t, J = 7.0 Hz), 2.31-2.51 (4H, m), 3.28-3.70 (10H, m), 3.74 (3H, s), 4.01 (2H, s), 5.95 (2H, s), 6.22 (1H, dd, J = 8.7 Hz, 2.8 Hz), 6.35 (1H, d, J = 2.8 Hz), 6.68 (1H dd, J = 8.7 Hz, 0.5 Hz), 6.69-6.79 (2H, m), 6.81-6.88 (1H, m), 6.93 (1H, d, J = 8.7 Hz), 7.03 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.65 (1H, dd, J = 3.0 Hz, 0.5 Hz). 465 —CH₃ —CH₃ —H 2.13 (3H, s), 2.42 (4H, t, J = 3.0 Hz), 2.99 (3H, s), 3.35- 3.57 (6H, m), 3.58-3.70 (2H, m), 4.05 (2H, s), 5.95 (2H, s), 6.53 (1H, dd, J = 8.8 Hz, 3.1 Hz), 6.57 (1H, d, J = 3.1 Hz), 6.60 (1H, d, J = 8.8 Hz), 6.71-6.78 (2H, m), 6.85 (1H, brs), 6.88 (1H, d, J = 8.7 Hz), 7.02 (1H, dd, J =8.7 Hz, 3.0 Hz), 7.67 (1H, d, J = 3.0 Hz). 466 —CH₃ —C₂H₅ —H 1.15 (3H, t, J = 7.0 Hz), 2.12 (3H, s), 2.42 (4H, t, J = 5.1 Hz), 3.27-3.70 (10H, m), 4.00 (2H, s), 5.95 (2H, s), 6.46-6.57 (2H, m), 6.60 (1H, dd, J = 8.7 Hz, 0.5 Hz), 6.69-6.78 (2H, m), 6.82- 6.90 (2H, m), 7.02 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.68 (1H, dd, J = 3.0 Hz, 0.5 Hz). 467 —CH₃ —Ac —H 1.95 (3H, s), 2.23 (3H, s), 2.31-2.52 (4H, m), 3.29-3.70 (8H, m), 4.43 (2H, s), 5.94 (2H, s), 6.69-6.79 (3H, m), 6.84 (1H, s), 6.92 (1H, d, J = 8.5 Hz), 7.10 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.19 (1H, dd, J = 8.5 Hz, 2.5 Hz), 7.28 (1H, d, J = 2.2 Hz), 7.68 (1H, d, J = 2.5 Hz).

TABLE 66

Reference Example No. R₂₄₂ R₂₄₃ Xa₁₆ M E ¹H NMR (solvent) δ ppm 468 —OCH₃ —H —CH₂— 1 1 (DMSO-d₆) 2.32-2.40 (4H, m), 3.32 (2H, brs), 3.50 (4H, brs), 3.61 (3H, s), 3.88 (2H, brs), 4.88 (2H, brs), 5.44 (1H, brs), 5.99 (2H, s), 6.15 (1H, dd, J = 8.6 Hz, 2.5 Hz), 6.44 (1H, d, J = 2.3 Hz), 6.51 (1H, d, J = 8.6 Hz), 6.71- 6.88 (4H, m), 6.98 (1H, dd, J = 8.6 Hz, 2.8 Hz), 7.40 (1H, d, J = 2.6 Hz). 469 —OCH₃ —H —CH₂— 1 2 (DMSO-d₆) 2.32 (2H, brs), 2.40 (2H, brs), 3.39 (2H, s), 3.49 (4H, brs), 3.61 (3H, s), 3.89 (2H, brd), 4.22 (4H, s), 4.82 (2H, brs), 5.44 (1H, brt), 6.15 (1H, dd, J = 8.6 Hz, 2.5 Hz), 6.44-6.52 (2H, m), 6.70-6.81 (4H, m), 6.98 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.39 (1H, d, J = 2.8 Hz). 470 —H —CH₃ —CH₂— 2 1 (CDCl₃) 2.35 (4H, tt, J = 5.0 Hz, 5.0 Hz), 2.52-2.58 (2H, m), 2.91 (3H, s), 3.36-3.39 (4H, m), 3.59-3.62 (2H, m), 3.65-3.73 (4H, m), 5.93 (2H, s), 6.64-6.76 (5H, m), 6.83 (1H, d, J = 1.0 Hz), 6.97 (2H, d, J = 9.1 Hz), 7.03 (1H, dd, J = 8.6 Hz, 3.1 Hz), 7.66 (1H, dd, J = 3.1 Hz, 0.5 Hz). 471 —CH₃ —CH₃ —CO— 1 1 (CDCl₃) 2.12 (3H, s), 2.88-3.10 (3H, m), 3.26 (2H, t, J = 5.3 Hz), 3.40 (2H, brs), 3.60- 3.90 (2H, m), 4.00-4.15 (2H, m), 4.20- 4.40 (2H, m), 4.52 (2H, s), 5.95 (2H, s), 6.53 (1H, dd, J = 8.5 Hz, 3.0 Hz), 6.60 (1H, s), 6.60 (1H, d, J = 8.5 Hz), 6.71 (1H, d, J = 8.5 Hz), 6.74 (1H, s), 6.76 (1H, d, J = 8.5 Hz), 6.88 (1H, d, J = 8.8 Hz), 7.02 (1H, dd, J = 8.5 Hz, 2.8 Hz), 7.66 (1H, d, J = 2.8 Hz). 472 —OCH₃ —C₂H₅ —CO— 1 1 (CDCl₃) 1.17 (3H, t, J = 7.0 Hz), 3.20- 3.31 (2H, m), 3.40-3.60 (2H, m), 3.41 (2H, q, J = 7.0 Hz), 3.61-3.82 (2H, m), 3.74 (3H, s), 4.02 (2H, s), 4.30 (2H, s), 4.50 (2H, s), 5.95 (2H, s), 6.24 (1H, dd, J = 8.7 Hz, 2.8 Hz), 6.40 (1H, s), 6.68 (1H, d, J = 8.6 Hz), 6.70 (1H, dd, J = 7.9 Hz, 1.5 Hz), 6.76 (1H, d, J = 1.5 Hz), 6.76 (1H, d, J = 7.9 Hz), 6.93 (1H, d, J = 8.6 Hz), 7.03 (1H, dd, J = 8.5 Hz, 2.8 Hz), 7.64 (1H, d, J = 2.8 Hz). (E means the number of the methylene groups. Hereinafter E indicates the same meaning.)

TABLE 67

Reference Example No. Xa₁₇ M E R₂₄₄ Form mp (° C.) or ¹H NMR (CDCl₃) δppm 473 —CH₂— 1 0 benzyl free ¹H NMR 2.33-2.43(4H, m), 2.57-2.63 (2H, m), 2.91-2.97(2H, m), 3.38- 3.42(4H, m), 3.50(2H, s), 3.62- 3.65(2H, m), 6.75(1H, dd, J = 8.6 Hz, 0.5 Hz), 6.95-7.00(2H, m), 7.07(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.15-7.20(2H, m), 7.28-7.33(5H, m), 7.70(1H, dd, J = 3.0 Hz, 0.5 Hz). 474 —CH₂— 1 0 piperonyl trihydro- mp 179-180 dec chloride 475 —O— 1 0 piperonyl free ¹H NMR 2.41(4H, brs), 3.42(2H, s), 3.48(2H, brs), 3.50-3.70(4H, m), 4.65(2H, s), 5.95(2H, s), 6.72(1H, d, J = 8.6 Hz), 6.74(2H, brs), 6.85(1H, brs), 6.91(2H, d, J = 9.2 Hz), 7.00(2H, d, J = 9.2 Hz), 7.06(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.69(1H, d, J = 3.0 Hz). 476 —O— 1 0 benzyl free ¹H NMR 2.44(4H, t, J = 5.0 Hz), 3.51(4H, s), 3.58(2H, t, J = 5.0 Hz), 3.64(2H, t, J = 5.0 Hz), 4.65(2H, s), 6.72(1H, d, J = 8.5 Hz), 6.92(2H, d, J = 9.2 Hz), 7.00(2H, d, J = 9.2 Hz), 7.06(1H, dd, J = 8.5 Hz, 3.0 Hz), 7.22-7.35(5H, m), 7.69(1H, d, J = 3.0 Hz). 477 —NH— 0 1 piperonyl free ¹H NMR 2.51(4H, brs), 2.62-2.63(4H, m), 3.12(2H, s), 3.45(2H, s), 3.52(2H, brs), 5.94(2H, s), 6.74(1H, dd, J = 8.7 Hz, 0.7 Hz), 6.75(2H, brs), 6.85(1H, s), 7.03(2H, d, J = 8.9 Hz), 7.07(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.54(2H, d, J = 9.1 Hz), 7.69(1H, dd, J = 3.0 Hz, 0.7 Hz), 9.10(1H, brs). 478 —N(CH₃)— 0 1 piperonyl free ¹H NMR 2.44(8H, brs), 2.93(2H, s), 3.24(3H, s), 3.38(2H, s), 3.62(2H, brs), 5.92(2H, s), 6.72(2H, brs), 6.80- 6.84(2H, m), 7.06(2H, d, J = 9.1 Hz), 7.12(1H, dd, J = 8.6 Hz, 3.1 Hz), 7.15(2H, d, J = 8.9 Hz), 7.73(1H, d, J = 3.0 Hz).

TABLE 68

Reference Example No. R₂₄₅ R₂₄₆ R₂₄₇ ¹H NMR (CDCl₃) δppm 479 —CH₃ —H —CH₃ 1.12(3H, d, J = 6.3 Hz), 2.10-2.12(1H, m), 2.47(1H, brs), 2.67-2.72(1H, m), 2.80-3.11(6H, m), 3.47- 3.60(3H, m), 3.84-4.10(4H, m), 5.94(2H, s), 6.64- 6.74(5H, m), 6.85(1H, brs), 6.94-6.98(2H, m), 7.00- 7.05(1H, m), 7.68(1H, d, J = 2.8 Hz). 480 —CH₃ —CH₃ —H 1.28-1.37(3H, m), 1.94-2.03(1H, m), 2.11-2.15(1H, m), 2.63-2.67(1H, m), 2.79-2.82(1H, m), 2.95-3.00(4H, m), 3.30-3.46(5H, m), 4.03-4.69(3H, m), 5.94(2H, s). 6.66(1H, d, J = 8.7 H), 6.68(2H, d, J = 9.1 H), 6.74(2H, brs), 6.87(1H, brs), 6.96(2H, d, J = 9.1 Hz), 7.03(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.68(1H, d, J = 3.0 Hz). 481 —C₂H₅ —H —CH₃ 1.11-1.18(6H, m), 2.04-2.13(1H, m), 2.45-2.47(1H, m), 2.66-2.73(1H, m), 2.85-3.64(8H, m), 3.84-4.11(4H, m), 5.94(2H, s), 6.64-6.69(3H, m), 6.74(2H, brs), 6.85(1H, brs), 6.93-6.96(2H, m), 7.03(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.69(1H, d, J = 3.0 Hz). 482 —C₂H₅ —CH₃ —H 1.15(3H, t, J = 7.1 Hz), 1.26-1.70(3H, m), 1.94- 2.04(1H, m), 2.14-2.17(1H, m), 2.63-2.67(1H, m), 2.80(1H, brs), 3.01-3.59(8H, m), 3.73-4.71(3H, m), 5.95(2H, s), 6.63-6.70(3H, m), 6.74(2H, brs), 6.87(1H, brs), 6.95(2H, d, J = 9.1 Hz), 7.03(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.69(1H, dd, J = 3.0 Hz, 0.7 Hz).

TABLE 69

Reference Example No. R₂₄₈ ¹H NMR (CDCl₃) δppm 483 piperonyl 1.36-1.46(2H, m), 1.82-1.99(3H, m), 2.13(3H, s), 2.28(2H, d, J = 6.8 Hz), 2.41(4H, brs), 2.70(2H, t, J = 12.0 Hz), 3.41-3.76(10H, m), 5.94(2H, s), 6.59-6.89(7H, m), 7.03(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.67-7.69(1H, m). 484 benzyl 1.33-1.42(2H, m), 1.82-1.98(3H, m), 2.04(3H, s), 2.28(2H, d, J = 6.8 Hz), 2.41-2.45(4H, m), 2.70(2H, t, J = 12.0 Hz), 3.51-3.78(10H, m), 6.60(1H, d, J = 8.6 Hz), 6.69-6.92(3H, m), 7.03(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.28-7.33(5H, m), 7.67(1H, d, J = 2.5 Hz).

TABLE 70

Reference Example No. R₂₄₉ R₂₅₀ R₂₅₁ MS (M⁺) 485 —H —H —C₂H₅ 557 486 —H —CH₃ —CH₃ 557 487 —CH₃ —H —CH₃ 557

Reference Example 488 Production of ethyl {4-(4-amino-2-fluorophenoxy)phenylsulfanyl}acetate

To a solution of ethyl [4-(2-fluoro-4-nitrophenoxy)phenylsulfanyl]acetate (4.93 g, 14.0 mmol) in ethanol (100 mL) was added tin chloride dihydrate (9.50 g, 42.1 mmol), and the resulting solution was stirred for 8 hours at 50° C. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with 1 M hydrochloric acid, a saturated sodium bicarbonate solution, and brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 3.45 g of the title compound.

Appearance: Brown oil

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7.1 Hz), 3.53 (2H, s), 3.80-4.20 (4H, m), 6.37-6.45 (1H, m), 6.49 (1H, dd, J=2.6 Hz, 12.0 Hz), 6.80-7.00 (3H, m), 7.38 (2H, d, J=8.9 Hz).

The following compounds were produced in the same manner as in Reference Example 488.

Reference Example 489 2-{Allyl[4-(5-aminopyridin-2-yloxy)-3-fluorophenyl]amino}-1-(4-piperonylpiperazin-1-yl)ethanone

¹H NMR (CDCl₃) δ 2.44-2.46 (4H, m), 3.44 (4H, brs), 3.44 (2H, s), 3.83 (2H, brs), 3.98 (2H, d, J=4.8 Hz), 4.03 (2H, s), 5.16-5.30 (2H, m), 5.82-5.95 (1H, m), 5.95 (2H, s), 6.35-6.46 (2H, m), 6.71-6.74 (3H, m), 6.85-6.87 (1H, m), 6.96-7.07 (2H, m), 7.63-7.64 (1H, m).

Reference Example 490 (E)-3-[3-(5-Aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propenone

MS 458 (M⁺).

Reference Example 491 Production of methyl 3-[4-(5-aminopyridin-2-ylsulfanyl)phenyl]propionate

To a solution of methyl 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionate (2.97 g, 9.33 mmol) in methanol (50 mL) were added sodium borohydride (0.590 g, 15.6 mmol) and 10% palladium-carbon (1.80 g), and the resulting solution was stirred for 24 hours at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through Celite, and to the resulting filtrate was added concentrated hydrochloric acid (1.5 mL), and concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate, and the ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 2.49 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 2.62 (2H, t, J=7.6 Hz), 2.93 (2H, t, J=7.6 Hz), 3.67 (3H, s), 6.87 (1H, dd, J=2.9 Hz, 8.4 Hz), 6.98 (1H, d, J=8.4 Hz), 7.15 (2H, d, J=8.2 Hz), 7.35 (2H, d, J=8.2 Hz), 8.01 (1H, d, J=2.9 Hz).

Reference Example 492 Production of ethyl 3-[4-(5-aminopyridin-2-yloxy)phenyl]acrylate

To a solution of ethyl 3-[4-(5-nitropyridin-2-yloxy)phenyl]acrylate (2.02 g, 6.43 mmol) in methanol (100 mL) were added zinc (6.3 g, 96.3 mmol) and ammonium chloride (710 mg, 13.27 mmol). The resulting reaction solution was stirred for 2.5 hours under reflux, then acetic acid (5 mL) was added, and stirred for 20 minutes under reflux. Insoluble matter was filtered off through Celite, after which the filtrate was concentrated under reduced pressure. To the residue was added 5% potassium hydrogensulfate (150 mL), the mixture was extracted with dichloromethane, and the dichloromethane layer was washed with a saturated sodium bicarbonate solution and brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 1.78 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 1.34 (3H, t, J=7.1 Hz), 3.58 (2H, brs), 4.26 (2H, q, J=7.1 Hz), 6.35 (1H, dd, J=16.0 Hz, 2.0 Hz), 6.81 (1H, d, J=8.6 Hz), 7.05 (2H, d, J=8.6 Hz), 7.10 (1H, dd, J=8.6 Hz, 3.0 Hz), 7.50 (2H, d, J=8.6 Hz), 7.66 (1H, dd, J=16.0 Hz, 3.0 Hz), 7.73 (1H, d, J=3.0 Hz).

Reference Example 493 Production of 3-(4-(5-amino-4-methylpyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one

3-(4-hydroxyphenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one (0.38 g, 1.0 mmol) was dissolved in DMF (6 mL). To the resulting solution was added 60% sodium hydride (0.05 g, 1.2 mmol) and 2-chloro-4-methyl-5-nitropyridine (0.196 g, 1.1 mmol), and the resulting reaction solution was stirred overnight at room temperature. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield the intermediate product 3-(4-(4-methyl-5-nitropyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one. The 3-(4-(4-methyl-5-nitropyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one was dissolved in a mixed solvent consisting of ethanol (4 mL) and dioxane (1 mL). To this solution was added 10% palladium-carbon (0.034 g), and the resulting solution was subjected to catalytic reduction for 8 hours at atmospheric pressure and room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:methanol=20:1), to thereby yield 0.22 g of the title compound.

Appearance: Slightly yellow oil

¹H NMR (CDCl₃) δ 2.18 (3H, s), 2.30-2.45 (4H, m), 2.56-2.63 (2H, m), 2.91-2.97 (2H, m), 3.30-3.50 (6H, m), 3.55-3.70 (2H, m), 5.95 (2H, s), 6.65-6.80 (3H, m), 6.84 (1H, s), 6.95-7.05 (2H, m), 7.15-7.20 (2H, m), 7.64 (1H, s).

Reference Example 494 Production of ethyl 3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionate

A solution of 3,4-dichlorobenzoyl chloride (3.65 g, 17.4 mmol) was added dropwise under ice cooling to a solution of ethyl 3-[4-(4-aminophenoxy)phenyl]propionate (4.52 g, 15.9 mmol) and triethylamine (2.65 mL, 19.0 mmol) in THF (80 mL), and the resulting solution was stirred for 1 hour at the same temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from water-containing ethanol to thereby yield 6.67 g of the title compound.

Appearance: Colorless needles

Melting point: 139-141° C.

The following compounds were produced in the same manner as in Reference Example 494.

Reference Example 495 Ethyl 3-[4-(5-phenoxycarbonylaminopyridin-2-yloxy)phenyl]propionate

MS 406 (M⁺).

TABLE 71

Refer- ence Ex- ample mp No. Xa₁₈ R₂₅₂ (° C.) or ¹H NMR (CDCl₃) δppm 496 p- 2-(CH₂)₂COOCH₃ mp 117-119 phenylene 497 p- 3-(CH₂)₂COOC₂H₅ mp 111-113 phenylene 498 o- 4-(CH₂)₂COOC₂H₅ mp 72-73 phenylene 499 m- 4-(CH₂)₂COOC₂H₅ ¹H NMR 1.22(3H, t, J = 7.2 Hz), phenylene 2.59(2H, t, J = 7.7 Hz), 2.91(2H, t, J = 7.7 Hz), 4.10(2H, q, J = 7.2 Hz), 6.78(1H, dt, J = 8.1 Hz, 1.1 Hz), 6.93(2H, d, J = 8.5 Hz), 7.14(2H, d, J = 8.5 Hz), 7.20-7.36(3H, m), 7.52(1H, d, J = 8.3 Hz), 7.64(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.81(1H, brs), 7.91(1H, d, J = 2.1 Hz).

TABLE 72

Reference Example No. R₂₅₃ R₂₅₄ mp (° C.) or ¹H NMR (solvent) δppm 500 —F —H mp 168-169 501 —H —COOC₂H₅ mp 144-145 502 —F —COOC₂H₅ mp 145-146 503 —F —CH₂COOCH₃ mp 127-129 504 —F —(CH₂)₂COOC₂H₅ mp 131-133 505 —F —(CH₂)₃COOC₂H₅ mp 110-111 506 —F —SCH₂COOC₂H₅ ¹H NMR (CDCl₃) 1.23(3H, t, J = 7.1 Hz), 3.56(2H, s), 4.15(2H, q, J = 7.1 Hz), 6.90(2H, d, J = 8.7 Hz), 7.08(1H, t, J = 8.7 Hz), 7.20-7.30(1H, m), 7.42(2H, d, J = 8.7 Hz), 7.58(1H, d, J = 8.3 Hz), 7.65- 7.80(2H, m), 7.82(1H, s), 7.96(1H, d, J = 2.1 Hz). 507 —F —NHCH₂COOC₂H₅ ¹H NMR (DMSO-d₆) 1.19(3H, t, J = 7.1 Hz), 3.87(2H, d, J = 6.4 Hz), 4.11(2H, q, J = 7.1 Hz), 5.93(1H, t, J = 6.4 Hz), 6.56(2H, d, J = 9.0 Hz), 6.81(2H, d, J = 9.0 Hz), 6.98(1H, t, J = 9.2 Hz), 7.44-7.47(1H, m), 7.82-7.86(2H, m), 7.93(1H, dd, J = 2.0 Hz, 8.4 Hz), 8.20(1H, d, J = 2.0 Hz), 10.50(1H, s). 508 —H —Br ¹H NMR (DMSO-d₆) 6.96(2H, d, J = 9.0 Hz), 7.08(2H, d, J = 9.0 Hz), 7.55(2H, d, J = 8.5 Hz), 7.79(2H, d, J = 8.5 Hz), 7.83(1H, d, J = 8.5 Hz), 7.94(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1H, d, J = 2.0 Hz), 10.44(1H, brs). 509 —F —Ac mp 143 510 —F

¹H NMR (CDCl₃) 4.00-4.15(4H, m), 5.78(1H, s), 6.96(2H, d, J = 8.7 Hz), 7.00-7.10(1H, m), 7.20- 7.30(1H, m), 7.43(2H, d, J = 8.7 Hz), 7.57(1H, d, J = 8.3 Hz), 7.82(1H, s), 7.95(1H, d, J = 2.1 Hz).

TABLE 73

Reference Example No. R₂₅₅ R₂₅₆ R₂₅₇ ¹H NMR (CDCl₃) δppm 511 —Cl —Cl

3.98(3H, s), 7.06(1H, d, J = 8.7 Hz), 7.33-7.37(1H, m), 7.56-7.59(2H, m), 7.70-7.73(1H, m), 7.80(1H, d, J = 8.5 Hz), 7.95-8.07(4H, m), 8.23-8.30(2H, m), 8.60(1H, s). 512 —CF₃ —H

3.98(3H, s), 7.07-7.10(1H, m), 7.37(1H, dd, J = 8.9 Hz, 2.3 Hz), 7.58(1H, d, J = 2.3 Hz), 7.76- 7.82(3H, m), 7.93-8.08(5H, m), 8.27- 8.31(2H, m), 8.60(1H, s). 513 —Cl —Cl

1.46(3H, t, J = 7.1 Hz), 4.47(2H, q, J = 7.1 Hz), 7.04(1H, d, J = 8.7 Hz), 7.41(1H, dd, J = 9.4 Hz, 2.5 Hz), 7.47-7.60(3H, m), 7.70(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.82(1H, brs), 7.94(1H, d, J = 8.6 Hz), 7.98(1H, d, J = 2.1 Hz), 8.14(1H, dd, J = 7.3 Hz, 1.2 Hz), 8.20-8.27(2H, m), 8.92(1H, d, J = 9.4 Hz). 514 —CF₃ —H

1.46(3H, t, J = 7.1 Hz), 4.47(2H, q, J = 7.1 Hz), 7.04(1H, d, J = 8.7 Hz), 7.40(1H, dd, J = 9.4 Hz, 2.5 Hz), 7.47-7.53(1H, m), 7.59(1H, d, J = 2.5 Hz), 7.75(2H, d, J = 8.2 Hz), 7.92- 8.00(4H, m), 8.14(1H, dd, J = 7.3 Hz, 1.2 Hz), 8.23-8.29(2H, m), 8.97(1H, d, J = 9.4 Hz). 515 —Cl —Cl

4.00(3H, s), 7.09(1H, d, J = 9.6 Hz), 7.16(1H, d, J = 8.1 Hz), 7.50- 7.57(2H, m), 7.62-7.72(2H, m), 7.98(2H, d, J = 2.1 Hz), 8.15- 8.29(4H, m), 9.01(1H, d, J = 8.7 Hz).

TABLE 74

Reference Example No. R₂₅₈ ¹H NMR (CDCl₃) δppm 516 —COOCH₃ 3.91(3H, s), 7.03(1H, d, J = 8.9 Hz), 7.15-7.18(2H, m), 7.58(1H, d, J = 8.3 Hz), 7.69-7.73(1H, m), 7.89(1H, brs), 7.99(1H, d, J = 2.0 Hz), 8.06-8.09(2H, m), 8.23-8.30(2H, m). 517 —COOC₂H₅ 1.39(3H, t, J = 7.3 Hz), 4.37(2H, q, J = 7.3 Hz), 7.02(1H, d, J = 8.6 Hz), 7.15-7.18(2H, m), 7.57(1H, d, J = 8.6 Hz), 7.70-7.73(1H, m), 7.97-7.99(2H, m), 8.06-8.09(2H, m), 8.23-8.30(2H, m) 518 —CH₂COOCH₃ 3.63(2H, s), 3.71(3H, s), 6.94(1H, d, J = 8.9 Hz), 7.07(2H, d, J = 8.2 Hz), 7.30(2H, d, J = 8.6 Hz), 7.55(1H, d, J = 8.6 Hz), 7.70(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.97-8.08(2H, m), 8.17(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz). 519 —(CH₂)₂COOCH₃ 2.62-2.67(2H, m), 2.93-2.98(2H, m), 3.68(3H, s), 6.93 (1H, d, J = 8.9 Hz), 7.03-7.06(2H, m), 7.20-7.23(2H, m), 7.56(1H, d, J = 8.3 Hz), 7.68-7.72(1H, m), 7.96-7.98(2H, m), 8.17(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz). 520 —(CH₂)₃COOC₂H₅ 1.26(3H, t, J = 7.0 Hz), 1.96(2H, dt, J = 15.0 Hz, 7.5 Hz), 2.34(2H, t, J = 7.5 Hz), 2.66(2H, t, J = 7.5 Hz), 4.13(2H, q, J = 7.0 Hz), 6.93(1H, d, J = 8.8 Hz), 7.04(2H, d, J = 8.6 Hz), 7.20(2H, d, J = 8.6 Hz), 7.56(1H, d, J = 8.3 Hz), 7.70(1H, dd, J = 8.3 Hz, 2.0 Hz) ,7.89(1H, s), 7.98(1H, d, J = 2.0 Hz), 8.16(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz). 521 —(CH₂)₄COOC₂H₅ 1.26(3H, t, J = 7.2 Hz), 1.60-1.75(4H, m), 2.33(2H, t, J = 7.0 Hz), 2.64(2H, t, J = 7.0 Hz), 4.13(2H, q, J = 7.2 Hz), 6.94(1H, d, J = 8.9 Hz), 7.04(2H, d, J = 8.5 Hz), 7.20(2H, d, J = 8.5 Hz), 7.58(1H, d, J = 8.3 Hz), 7.70(1H, dd, J = 8.3 Hz, 2.3 Hz), 7.78(1H, brs), 7.98(1H, d, J = 2.3 Hz), 8.16(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz). 522 —CH₂CN 3.76(2H, s), 7.00(1H, d, J = 8.8 Hz), 7.16(2H, d, J = 8.7 Hz), 7.37(2H, d, J = 8.7 Hz), 7.58(1H, d, J = 8.4 Hz), 7.70(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.81(1H, s), 7.98(1H, d), J = 2.1 Hz), 8.20(1H, dd, J = 8.8 Hz, 2.3 Hz), 8.25(1H, d, J = 2.3 Hz). 523 —NHCOOC(CH₃)₃ 1.52(9H, s), 6.49(1H, brs), 6.90(1H, d, J = 8.6 Hz), 7.05(2H, d, J = 8.9 Hz), 7.37(2H, d, J = 8.9 Hz), 7.56(1H, d, J = 8.6 Hz), 7.69(1H, dd, J = 8.6 Hz, 2.3 Hz), 7.92(1H, brs), 7.97(1H, d, J = 2.3 Hz), 8.14(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.22(1H, d, J = 2.6 Hz). 524 —CH═C(COOCH₃)₂ 3.85(3H, s), 3.86(3H, s), 7.02(1H, d, J = 8.8 Hz), 7.13(2H, d, J = 8.5 Hz), 7.46(2H, d, J = 8.5 Hz), 7.59(1H, d, J = 8.2 Hz), 7.70(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.74(1H, s), 7.88(1H, brs), 7.97(1H, d, J = 2.0 Hz), 8.22(1H, dd, J = 8.8 Hz, 2.5 Hz), 8.24(1H, d, J = 2.5 Hz).

TABLE 75

Reference Example No. R₂₅₉ R₂₆₀ R₂₆₁ ¹H NMR (solvent) δppm 525 —OCH₃ —H —COOC₂H₅ (CDCl₃) 1.40(3H, t, J = 7.1 Hz), 3.81(3H, s), 4.39(2H, q, J = 7.1 Hz), 6.99-7.02(1H, m), 7.16(1H, d, J = 8.1 Hz), 7.56(1H, d, J = 8.4 Hz), 7.67-7.72(3H, m), 7.97-8.01(2H, m), 8.17-8.22(2H, m). 526 —CH₃ —H —COOCH₃ (CDCl₃) 2.24(3H, s), 3.91(3H, s), 6.97- 7.01(1H, m), 7.07(1H, d, J = 8.4 Hz), 7.57(1H, d, J = 8.4 Hz), 7.69-7.73(1H, m), 7.91(1H, dd, J = 8.4 Hz, 2.4 Hz), 7.97- 7.99(3H, m), 8.21-8.26(2H, m). 527 —Cl —H —COOCH₃ (CDCl₃) 3.93(3H, s), 7.08(1H, d, J = 8.7 Hz), 7.26(1H, d, J = 1.7 Hz), 7.56(1H, d, J = 8.2 Hz), 7.69-7.73(1H, m), 7.95-7.99(2H, m), 8.10(1H, brs), 8.15(1H, d, J = 2.0 Hz) ,8.22- 8.24(1H, m), 8.27(1H, d, J = 2.8 Hz). 528 —F —H —COOCH₃ (CDCl₃) 3.92(3H, s), 7.07(1H, dd, J = 7.8 Hz, 1.8 Hz), 7.25-7.31(1H, m), 7.56(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.2 Hz, 2.1 Hz), 7.82- 7.89(2H, m), 7.97(1H, d, J = 2.1 Hz), 8.08(1H, brs), 8.21-8.25(2H, m). 529 —H —OCH₃ —COOCH₃ (CDCl₃) 3.83(3H, s), 3.87(3H, s), 6.70(1H, dd, J = 8.6 Hz, 2.2 Hz), 6.74(1H, d, J = 2.2 Hz), 7.01(1H, d, J = 8.6 Hz), 7.56(1H, d, J = 8.1 Hz), 7.75(1H, dd, J = 8.6 Hz, 2.2 Hz), 7.87(1H, d, J = 8.6 Hz), 8.01(1H, d, J = 2.2 Hz), 8.25-8.33(3H, m). 530 —H —CH₃ —COOCH₃ (CDCl₃) 2.63(3H, s), 3.91(3H, s), 6.98- 7.05(3H, m), 7.60(1H, d, J = 8.4 Hz), 7.75(1H, dd, J = 8.4 Hz, 2.2 Hz), 7.97- 8.03(3H, m), 8.23-8.28(1H, m), 8.30-8.32(1H, m). 531 —H —COOCH₃ —H (DMSO-d₆) 3.85(3H, s), 7.17(1H, d, J = 8.9 Hz), 7.43-7.47(1H, m), 7.56-7.62(2H, m), 7.78-7.86(2H, m), 7.93-7.97(1H, m), 8.22- 8.27(2H, m), 8.50(1H, d, J = 2.3 Hz), 10.60(1H, s).

TABLE 76

Reference Example No. R₂₆₂ R₂₆₃ R₂₆₄ ¹H NMR (CDCl₃) δppm 532 —OCH₃ —H —COOC₂H₅ 1.40(3H, t, J = 7.1 Hz), 3.82(3H, s), 4.39(2H, q, J = 7.1 Hz), 7.00-7.03(1H, m), 7.17(1H, d, J = 8.1 Hz), 7.68- 7.76(4H, m), 8.01(2H, d, J = 8.1 Hz), 8.16(1H, brs), 8.22-8.25(2H, m). 533 —OCH₃ —H —(CH₂)₂COOCH₃ 2.63-2.69(2H, m), 2.93-2.99(2H, m), 3.69(3H, s), 3.74(3H, s), 6.78-6.84(2H, m), 6.93(1H, d, J = 8.7 Hz), 7.03(1H, d, J = 8.1 Hz), 7.73(2H, d, J = 8.1 Hz), 7.96-7.99(3H, m), 8.14-8.20(2H, m). 534 —CH₃ —H —COOCH₃ 2.25(3H, s), 3.91(3H, s), 6.99-7.03(1H, m), 7.07(1H, d, J = 8.4 Hz), 7.75- 7.78(2H, m), 7.88-7.92(1H, m), 7.98- 8.01(4H, m), 8.26-8.29(2H, m). 535 —Cl —H —COOCH₃ 3.93(3H, s), 7.09(1H, d, J = 8.7 Hz), 7.24-7.27(1H, m), 7.76(2H, d, J = 8.7 Hz), 7.96-8.03(4H, m), 8.16(1H, d, J = 2.1 Hz), 8.24(1H, d, J = 2.6 Hz), 8.29(1H, dd, J = 8.7 Hz, 2.6 Hz). 536 —F —H —COOCH₃ 3.92(3H, s), 7.08(1H, d, J = 8.7 Hz), 7.26-7.32(1H, m), 7.75(2H, d, J = 8.4 Hz), 7.83-7.90(2H, m), 7.98(3H, d, J = 8.2 Hz), 8.22-8.28(2H, m). 537 —H —OCH₃ —COOCH₃ 3.87(3H, s), 3.88(3H, s), 6.71(1H, dd, J = 8.6 Hz, 2.2 Hz), 6.77(1H, d, J = 2.2 Hz), 7.04(1H, d, J = 8.9 Hz), 7.77(2H, d, J = 8.1 Hz), 7.88(1H, d, J = 8.6 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.17(1H, brs), 8.29- 8.35(2H, m). 538 —H —CH₃ —COOCH₃ 2.63(3H, s), 3.91(3H, s), 6.98-7.06(3H, m), 7.79(2H, d, J = 8.1 Hz), 8.00- 8.04(4H, m), 8.27-8.34(2H, m). 539 —H —COOCH₃ —H 3.91(3H, s), 6.99-7.04(1H, m), 7.32- 7.37(1H, m), 7.45-7.50(1H, m), 7.74- 7.80(3H, m), 7.86-7.90(1H, m), 7.96- 8.01(3H, m), 8.22-8.27(2H, m).

TABLE 77

Reference Example No. R₂₆₅ R₂₆₆ R₂₆₇ R₂₆₈ ¹H NMR (CDCl₃) δppm or mp (□) 540 —CF₃ —H —H

¹H NMR 1.17(3H, t, J = 7.1 Hz), 1.26(3H, d, J = 7.0 Hz), 2.44-2.61(2H, m), 3.19- 3.29(1H, m), 4.05(2H, q, J = 7.1 Hz), 6.88(1H, d, J = 8.8 Hz), 7.01(2H, d, J = 8.5 Hz), 7.19(2H, d, J = 8.5 Hz), 7.68(2H, d, J = 8.3 Hz), 7.94(2H, d, J = 8.3 Hz), 8.15(1H, dd, J = 8.8 Hz, 2.7 Hz), 8.23(1H, d, J = 2.7 Hz), 8.29(1H, brs). 541 —Cl —Cl —H

¹H NMR 1.17(3H, t, J = 7.1 Hz), 1.26(3H, d, J = 7.0 Hz), 2.43-2.60(2H, m), 3.18- 3.28(1H, m), 4.05(2H, q, J = 7.1 Hz), 6.85(1H, d, J = 8.9 Hz), 6.99(2H, d, J = 8.4 Hz), 7.18(2H, d, J = 8.4 Hz), 7.48(1H, d, J = 8.3 Hz), 7.66(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.92(1H, d, J = 2.0 Hz), 8.10(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.20(1H, d, J = 2.7 Hz), 8.39(1H, brs) 542 —CF₃ —H —H

¹H NMR 1.35(3H, t, J = 7.1 Hz), 4.27(2H, q, J = 7.1 Hz), 6.39(1H, dd, J = 16.0 Hz, 2.6 Hz), 7.03(1H, d, J = 8.9 Hz), 7.16(2H, d, J = 8.8 Hz), 7.56(2H, d, J = 8.8 Hz), 7.68(1H, dd, J = 16.0 Hz, 3.2 Hz), 7.77(2H, d, J = 8.1 Hz), 7.93(1H, brs), 8.01(2H, d, J = 8.1 Hz), 8.26(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.29(1H, d, J = 2.6 Hz). 543 —CF₃ —H —H —CH₂COOCH₃ ¹H NMR 3.62(2H, s), 3.70(3H, s), 6.94(1H, d, J = 8.7 Hz), 7.05-7.09(2H, m), 7.26-7.32(2H, m), 7.72(2H, d, J = 8.6 Hz), 7.97(2H, d, J = 8.2 Hz), 8.17-8.26(3H, m). 544 —CF₃ —H —H —(CH₂)₂COOC₂H₅ ¹H NMR 1.25(3H, t, J = 7.1 Hz), 2.62(2H, t, J = 7.7 Hz), 2.95(2H, t, J = 7.7 Hz), 4.13(2H, q, J = 7.1 Hz), 6.94(1H, d, J = 8.8 Hz), 7.04(2H, d, J = 8.6 Hz), 7.22(2H, d, J = 8.6 Hz), 7.75(2H, d, J = 8.3 Hz), 7.98(2H, d, J = 8.3 Hz), 8.03(1H, brs), 8.19(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.26(1H, d, J = 2.6 Hz). 545 —Cl —Cl —H

¹H NMR 0.01(6H, s), 0.89(9H, s), 2.83(2H, t, J = 6.9 Hz), 3.82(2H, t, J = 6.9 Hz), 6.92(1H, d, J = 8.9 Hz), 7.05(2H, dd, J = 6.3 Hz, 2.0 Hz), 7.24(2H, d, J = 8.6 Hz), 7.58(1H, d, J = 8.3 Hz), 7.71(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.80(1H, brs), 7.98(1H, d, J = 2.0 Hz), 8.15-8.19(1H, m), 8.25(1H, d, J = 2.6 Hz). 546 —Cl —Cl —H

¹H NMR 0.07(6H, s), 0.91(9H, s), 1.82- 1.87(2H, m), 2.65-2.71(2H, m), 3.63- 3.68(2H, m), 6.92(1H, d, J = 8.9 Hz), 7.02-7.05(2H, m), 7.21(2H, d, J = 8.6 Hz), 7.57(1H, d, J = 8.3 Hz), 7.68-7.72(1H, m), 7.86(1H, brs), 7.97(1H, d, J = 2.0 Hz), 8.14-8.18(1H, m), 8.24(1H, d, J = 2.3 Hz). 547 —H —F —CF₃ —COOC₂H₅ mp 133-134

TABLE 78

Reference Example No. R₂₆₉ R₂₇₀ Xa₁₉ R₂₇₁ M mp (° C.) or ¹H NMR (solvent) δppm 548 —Cl —Cl —S— —CH₃ 2 mp 141-142 549 —Cl —Cl —NH— —C₂H₅ 2 mp 170-171 550 —Cl —Cl —N(CH₃)— —C₂H₅ 2 ¹H NMR (DMSO-d₆) 1.17(3H, t, J = 7.1 Hz), 2.63(2H, t, J = 7.7 Hz), 2.85(2H, t, J = 7.7 Hz), 3.36(3H, s), 4.07(2H, d, J = 7.1 Hz), 6.56(1H, d, J = 9.5 Hz), 7.18(2H, d, J = 8.3 Hz), 7.27(2H, d, J = 8.3 Hz), 7.75-7.95(3H, m), 8.20(1H, s), 8.47(1H, s), 10.26(1H, s). 551 —CF₃ —H —N(CH₃)— —C₂H₅ 0 mp 135-136 552 —CF₃ —H —N(CH₃)— —C₂H₅ 2 ¹H NMR (CDCl₃) 1.26(3H, t, J = 7.2 Hz), 2.65(2H, t, J = 8.0 Hz), 2.97(2H, t, J = 8.0 Hz), 3.45(3H, s), 4.16(2H, q, J = 7.2 Hz), 6.57(1H, d, J = 9.1 Hz), 7.18(2H, d, J = 8.3 Hz), 7.24(2H, d, J = 8.3 Hz), 7.35-7.45(1H, m), 7.65- 7.78(3H, m), 7.98(2H, d, J = 8.1 Hz), 8.28(1H, d, J = 2.5 Hz). 553 —Cl —Cl —N(CH₂Ph)— —C₂H₅ 2 ¹H NMR (CDCl₃) 1.23(3H, t, J = 7.2 Hz), 2.61(2H, t, J = 7.6 Hz), 2.92(2H, t, J = 7.6 Hz), 4.12(2H, q, J = 7.2 Hz), 5.20(2H, s), 6.54(1H, d, J = 9.1 Hz), 7.10-7.30(8H, m), 7.53(1H, d, J = 8.4 Hz), 7.60-7.75(3H, m), 7.94(1H, d, J = 1.3 Hz), 8.22(1H, d, J = 2.3 Hz). 554 —Cl —H —O— —CH₃ 0 ¹H NMR (CDCl₃) 3.91(3H, s), 7.04(1H, d, J = 9.9 Hz), 7.17(2H, d, J = 8.6 Hz), 7.49(2H, d, J = 8.6 Hz), 7.79(1H, brs), 7.83(2H, d, J = 8.6 Hz), 8.08(2H, d, J = 8.6 Hz), 8.27-8.29(2H, m). 555 —CF₃ —H —O— —C₂H₅ 0 ¹H NMR (CDCl₃) 1.39(3H, t, J = 7.3 Hz), 4.37(2H, q, J = 7.3 Hz), 7.04(1H, dd, J = 8.3 Hz, 1.3 Hz), 7.15-7.19(2H, m), 7.78(2H, d, J = 8.3 Hz), 7.91(1H, brs), 8.00(2H, d, J = 6.9 Hz), 8.07- 8.10(2H, m), 8.27-8.31(2H, m). 556 —H —OCF₃ —O— —CH₃ 0 ¹H NMR (CDCl₃) 3.91(3H, s), 7.02(1H, d, J = 8.7 Hz), 7.16(2H, d, J = 8.7 Hz), 7.42(1H, d, J = 8.2 Hz), 7.53(1H, t, J = 8.1 Hz), 7.76-7.81(2H, m), 8.05- 8.08(3H, m), 8.25-8.31(2H, m). 557 —H —CF₃ —O— —C₂H₅ 0 ¹H NMR (CDCl₃) 1.39(3H, t, J = 7.2 Hz), 4.37(2H, q, J = 7.2 Hz), 7.40(1H, d, J = 8.7 Hz), 7.09-7.20(2H, m), 7.66(1H, t, J = 7.8 Hz), 7.76-7.90(1H, m), 8.00(1H, brs), 8.00-8.10(3H, m), 8.10-8.18(1H, m), 8.20-8.35(2H, m).

TABLE 79

Reference Example No. R₂₇₂ R₂₇₃ M mp (° C.) or ¹H NMR (CDCl₃) δppm 558 —H —Ac 1 mp 178-179 559 —H —Ac 2 ¹H NMR 1.22(3H, t, J = 7.2 Hz), 1.86(3H, s), 2.58(2H, t, J = 7.3 Hz), 3.99(2H, t, J = 7.3 Hz), 4.07(2H, q, J = 7.2 Hz), 7.02(1H, d, J = 8.9 Hz), 7.15-7.20(4H, m), 7.58(1H, d, J = 8.4 Hz), 7.75(1H, dd, J = 2.1 Hz, 8.4 Hz), 8.02(1H, d, J = 2.1 Hz), 8.24(1H, dd, J = 2.7 Hz, 8.9 Hz), 8.28(1H, s), 8.32(1H, d, J = 2.7 Hz). 560 —H —CH₃ 1 ¹H NMR 1.26(3H, t, J = 7.1 Hz), 8.06(3H, s), 4.04(2H, s), 4.18(2H, q, J = 7.1 Hz), 6.68(2H, d, J = 9.1 Hz), 6.85(1H, d, J = 8.9 Hz), 7.00(2H, d, J = 9.1 Hz), 7.55(1H, d, J = 8.4 Hz), 7.70(1H, dd, J = 1.9 Hz, 8.4 Hz), 7.94(1H, s), 7.97(1H, d, J = 1.9 Hz), 8.10(1H, dd, J = 2.6 Hz, 8.9 Hz), 8.21(1H, d, J = 2.6 Hz). 561 —H —C₂H₅ 1 ¹H NMR 1.22(3H, t, J = 7.1 Hz), 1.27(3H, t, J = 7.1 Hz), 3.46(2H, q, J = 7.1 Hz), 4.01(2H, s), 4.20(2H, q, J = 7.1 Hz), 6.64(2H, d, J = 9.1 Hz), 6.86(1H, d, J = 8.9 Hz), 6.98(2H, d, J = 9.1 Hz), 7.56(1H, d, J = 8.4 Hz), 7.70(1H, dd, J = 1.9 Hz, 8.4 Hz), 7.82(1H, s), 7.97(1H, d, J = 1.9 Hz), 8.11(1H, dd, J = 2.6 Hz, 8.9 Hz), 8.22(1H, d, J = 2.6 Hz). 562 —OCH₃ —CH₃ 1 ¹H NMR 1.25(3H, t, J = 7.1 Hz), 3.03(3H, s), 3.65(3H, s), 4.01(2H, s), 4.17(2H, q, J = 7.1 Hz), 6.16(1H, d, J = 8.7 Hz), 6.21(1H, s), 6.76(1H, d, J = 8.9 Hz), 6.88(1H, d, J = 8.6 Hz), 7.43(1H, d, J = 8.4 Hz), 7.67(1H, d, J = 8.4 Hz), 7.94(1H, d, J = 1.8 Hz), 8.02(1H, d, J = 8.9 Hz), 8.13(1H, d, J = 2.3 Hz), 8.88(1H, s). 563 —OCH₃ —C₂H₅ 1 ¹H NMR 1.21(3H, t, J = 7.1 Hz), 1.27(3H, t, J = 7.1 Hz), 3.44(2H, q, J = 7.1 Hz), 3.68(3H, s), 3.98(2H, s), 4.20(2H, q, J = 7.1 Hz), 6.17(1H, dd, J = 8.9 Hz, 3.0 Hz), 6.24(1H, d, J = 2.8 Hz), 6.81(1H, d, J = 8.9 Hz), 6.91(1H, d, J = 8.7 Hz), 7.48(1H, d, J = 8.4 Hz), 7.68(1H, dd, J = 8.4 Hz, 2.2 Hz), 7.96(1H, d, J = 2.0 Hz), 8.04(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.15(1H, d, J = 2.3 Hz), 8.34(1H, s). 564 —CH₃ —Ac 1 ¹H NMR 1.26(3H, t, J = 7.1 Hz), 1.96(3H, s), 2.22(3H, s), 4.20(2H, q, J = 7.1 Hz), 4.37(2H, s), 6.99(1H, d, J = 8.9 Hz), 7.07(1H, d, J = 8.4 Hz), 7.19(1H, dd, J = 2.4 Hz, 8.4 Hz), 7.59(1H, d, J = 8.4 Hz), 7.72(1H, d, J = 8.4 Hz), 7.90-8.12(2H, m), 8.21(1H, dd, J = 2.0 Hz, 8.4 Hz), 8.27(1H, s). 565 —CH₃ —CH₃ 1 ¹H NMR 1.26(3H, t, J = 7.1 Hz), 2.12(3H, s), 3.06(3H, s), 4.04(2H, s), 4.20(2H, q, J = 7.1 Hz), 6.49-6.61(1H, m), 6.83(1H, d, J = 8.9 Hz), 6.93(1H, d, J = 8.5 Hz), 7.57(1H, d, J = 8.5 Hz), 7.70(1H, dd, J = 8.5 Hz, 2.1 Hz), 7.73(1H, s), 7.97(1H, d, J = 2.1 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.21(1H, d, J = 2.8 Hz). 566 —F —Ac 1 ¹H NMR 1.29(3H, t, J = 7.1 Hz), 2.00(3H, s), 4.21(2H, q, J = 7.1 Hz), 4.37(2H, s), 7.09(1H, dd, J = 7.9 Hz, 1.8 Hz), 7.18-7.32(3H, m), 7.59(1H, d, J = 8.4 Hz), 7.72(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.83(1H, brs), 7.99(1H, d, J = 2.0 Hz), 8.20-8.24(2H, m). 567 —F —CH₃ 1 ¹H NMR 1.27(3H, t, J = 7.1 Hz), 3.06(3H, s), 4.04(2H, s), 4.20(2H, q, J = 7.1 Hz), 6.40-6.52(2H, m), 6.96(1H, d, J = 9.2 Hz), 7.07(1H, t, J = 9.1 Hz), 7.57(1H, d, J = 8.2 Hz), 7.70(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.82(1H, brs), 7.97(1H, d, J = 2.1 Hz), 8.13-8.19(2H, m). 568 —F —C₂H₅ 1 ¹H NMR 1.23(3H, t, J = 7.1 Hz), 1.28(3H, t, J = 7.1 Hz), 3.45(2H, q, J = 7.1 Hz), 4.00(2H, s), 4.22(2H, q, J = 7.1 Hz), 6.37-6.48(2H, m), 6.97(1H, d, J = 8.7 Hz), 7.05(1H, t, J = 9.1 Hz), 7.57(1H, d, J = 8.4 Hz), 7.70(1H, dd, J = 8.4 Hz, 2.2 Hz), 7.79(1H, brs), 7.98(1H, d, J = 2.0 Hz), 8.13-8.20(2H, m).

TABLE 80

Reference Example No. R₂₇₄ R₂₇₅ M E mp (° C.) or ¹H NMR (CDCl₃) δppm 569 —H —Ac 1 2 mp 163-164 570 —H —Ac 2 2 ¹H NMR 1.22(3H, t, J = 7.2 Hz), 1.87(3H, s), 2.59(2H, t, J = 7.3 Hz), 4.00(2H, t, J = 7.3 Hz), 4.08(2H, q, J = 7.2 Hz), 7.03(1H, d, J = 8.8 Hz), 7.19(4H, s), 7.78(2H, d, J = 8.3 Hz), 7.95(1H, brs), 8.01(2H, d, J = 8.3 Hz), 8.27(1H, d, J = 8.8 Hz), 8.31(1H, s). 571 —H —CH₃ 1 1 ¹H NMR 3.06(3H, s), 3.73(3H, s), 4.07(2H, s), 6.68(2H, d, J = 9.1 Hz), 6.86(1H, d, J = 8.9 Hz), 7.00(2H, d, J = 9.1 Hz), 7.74(2H, d, J = 8.0 Hz), 7.98(2H, d, J = 8.0 Hz), 8.07(1H, s), 8.15(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.24(1H, d, J = 2.5 Hz). 572 —H —C₂H₅ 1 2 ¹H NMR 1.18(3H, t, J = 7.1 Hz), 1.25(3H, t, J = 7.1 Hz), 3.41(2H, q, J = 7.1 Hz), 3.98(2H, s), 4.17(2H, q, J = 7.1 Hz), 6.59(2H, d, J = 9.1 Hz), 6.79(1H, d, J = 8.7 Hz), 6.92(2H, d, J = 9.1 Hz), 7.64(2H, d, J = 8.4 Hz), 7.94(2H, d, J = 8.1 Hz), 8.07(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, d, J = 2.8 Hz), 8.75(1H, s). 573 —OCH₃ —CH₃ 1 2 ¹H NMR 1.24(3H, t, J = 7.1 Hz), 3.03(3H, s), 3.65(3H, s), 4.01(2H, s), 4.17(2H, q, J = 7.1 Hz), 6.17(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.24(1H, d, J = 2.5 Hz), 6.77(1H, d, J = 8.9 Hz), 6.89(1H, d, J = 8.7 Hz), 7.63(2H, d, J = 8.3 Hz), 7.96(2H, d, J = 8.1 Hz), 8.06(1H, d, J = 8.7 Hz), 8.16(1H, d, J = 2.5 Hz), 8.91(1H, s). 574 —OCH₃ —C₂H₅ 1 2 ¹H NMR 1.19(3H, t, J = 7.1 Hz), 1.26(3H, t, J = 7.1 Hz), 3.42(2H, q, J = 7.1 Hz), 3.64(3H, s), 3.97(2H, s), 4.18(2H, q, J = 7.1 Hz), 6.14(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.21(1H, d, J = 2.8 Hz), 6.76(1H, d, J = 8.9 Hz), 6.87(1H, d, J = 8.7 Hz), 7.62(2H, d, J = 8.4 Hz), 7.96(2H, d, J = 8.3 Hz), 8.05(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.18(1H, d, J = 2.6 Hz), 9.01(1H, s). 575 —CH₃ —Ac 1 2 ¹H NMR 1.25(3H, t, J = 7.0 Hz), 1.93(3H, s), 2.21(3H, s), 4.18(2H, q, J = 7.0 Hz), 4.35(2H, s), 6.98(1H, d, J = 8.7 Hz), 7.06(1H, d, J = 8.5 Hz), 7.18(1H, d, J = 8.5 Hz), 7.23-7.28(1H, m), 7.75(2H, d, J = 7.8 Hz), 8.02(2H, d, J = 7.8 Hz), 8.22-8.33(2H, m). 576 —CH₃ —CH₃ 1 2 ¹H NMR 1.26(3H, t, J = 7.1 Hz), 2.11(3H, s), 3.05(3H, s), 4.04(2H, s), 4.19(2H, q, J = 7.1 Hz), 6.46-6.60(2H, m), 6.80(1H, d, J = 8.9 Hz), 6.91(1H, d, J = 8.5 Hz), 7.74(2H, d, J = 8.4 Hz), 7.98(2H, d, J = 8.2 Hz), 8.07(1H, s), 8.15 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.23(1H, d, J = 2.7 Hz). 577 —F —Ac 1 2 ¹H NMR 1.28(3H, t, J = 7.1 Hz), 1.98(3H, s), 4.20(2H, q, J = 7.1 Hz), 4.36(2H, s), 7.09(1H, dd, J = 6.4 Hz, 3.5 Hz), 7.13-7.32(3H, m), 7.77(2H, d, J = 8.3 Hz), 8.01(2H, d, J = 8.1 Hz), 8.12(1H, s), 8.23-8.28(2H, m). 578 —F —CH₃ 1 2 ¹H NMR 1.27(3H, t, J = 7.1 Hz), 3.07(3H, s), 4.04(2H, s), 4.20(2H, q, J = 7.1 Hz), 6.41-6.53(2H, m), 6.98(1H, d, J = 9.7 Hz), 7.07(1H, t, J = 9.1 Hz), 7.76(2H, d, J = 8.6 Hz), 7.84(1H, s), 7.99(2H, d, J = 8.1 Hz), 8.19-8.21(2H, m). 579 —F —C₂H₅ 1 2 ¹H NMR 1.20-1.31(6H, m), 3.45(2H, q, J = 7.3 Hz), 4.00(2H, s), 4.22(2H, q, J = 7.1 Hz), 6.37-6.49(2H, m), 6.97-7.09(2H, m), 7.76-7.79(3H, m), 7.99(2H, d, J = 7.9 Hz), 8.19-8.21(2H, m).

Reference Example 580 Production of ethyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]-3-methoxyphenyl}propionate

Under ice cooling, to a solution of ethyl 3-(4-(5-aminopyridin-2-yloxy)-3-methoxyphenyl)propionate (1.43 g, 4.5 mmol) in dichloromethane (30 mL) was added pyridine (0.44 mL, 5.4 mmol), and then 3,4-dichlorobenzoyl chloride (0.99 g, 4.7 mmol). The resulting solution was stirred for 1 hour under ice cooling, and then for 10 hours at room temperature. To the resulting reaction solution was added 10% hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated. To the residue was added diethyl ether, and stirred. The precipitates were collected by filtration. After washing with water and diethyl ether, the precipitates were air dried at 60° C., to thereby yield 0.52 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7.1 Hz), 2.56-2.79 (2H, m), 2.91-3.09 (2H, m), 3.75 (3H, s), 4.15 (2H, q, J=7.1 Hz), 6.75 (3H, m), 7.10 (1H, d, J=8.0 Hz), 7.56 (1H, d, J=8.2 Hz), 7.99 (1H, d, J=8.1 Hz), 8.17 (1H, s), 8.69 (1H, d, J=9.2 Hz), 8.79 (1H, s), 9.52 (1H, brs).

The following compounds were produced in the same manner as in Reference Example 580.

TABLE 81

Reference Example No. R₂₇₆ R₂₇₇ Xa₂₀ ¹H NMR (CDCl₃) δppm 581 3,4-Cl₂Ph— —H —CO— 1.23(3H, t, J = 7.2 Hz), 2.64(2H, t, J = 7.6 Hz), 3.01(2H, t, J = 7.6 Hz), 4.12(2H, q, J = 7.2 Hz), 7.30(2H, d, J = 8.2 Hz), 7.57(1H, d, J = 8.3 Hz), 7.73(1H, dd, J = 8.3 Hz, 2.2 Hz), 7.95-8.04 (3H, m), 8.09(1H, d, J = 8.6 Hz), 8.16(1H, brs), 8.41(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.80(1H, d, J = 2.6 Hz). 582 4-CF₃Ph— —OC₂H₅ —O— 1.22(3H, t, J = 6.9 Hz), 1.26(3H, t, J = 7.2 Hz), 2.51-2.73(2H, m), 2.87-3.06(2H, m), 4.02(2H, q, J = 6.9 Hz), 4.15(2H, q, J = 7.2 Hz), 6.71- 6.96(3H, m), 7.17(1H, d, J = 7.9 Hz), 7.75(2H, d, J = 7.6 Hz), 8.43(2H, d, J = 7.6 Hz), 9.15- 9.32(1H, m), 9.42(1H, s), 11.14(1H, brs). 583 3,4-Cl₂Ph— —F —O— 1.26(3H, t, J = 7.1 Hz), 2.53-2.70(2H, m), 2.85- 3.03(2H, m), 4.15(2H, q, J = 7.1 Hz), 6.97- 7.09(3H, m), 7.10-7.19(1H, m), 7.58(1H, d, J = 8.3 Hz), 7.70(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.72 (1H, brs), 7.97(1H, d, J = 2.1 Hz), 8.15- 8.23(2H, m). 584 PhCH₂O— —H —O— 1.25(3H, t, J = 7.1 Hz), 2.53-2.71(2H, m), 2.84- 3.04(2H, m), 4.14(2H, q, J = 7.1 Hz), 6.51- 6.64(1H, m), 6.88(1H, d, J = 8.8 Hz), 6.98- 7.06(2H, m), 7.17-7.24(2H, m), 7.30-7.43(5H, m), 7.87-8.02(1H, m), 8.05(1H, d, J = 2.5 Hz). 585 4-CF₃Ph— —F —O— 1.26(3H, t, J = 7.1 Hz), 2.56-2.71(2H, m), 2.89- 3.02(2H, m), 4.15(2H, q, J = 7.1 Hz), 6.97- 7.08(3H, m), 7.10-7.19(1H, m), 7.77(2H, d, J = 8.2 Hz), 7.82(1H, brs), 7.99(2H, d, J = 8.2 Hz), 8.17-8.26(2H, m).

TABLE 82

Reference Example No. R₂₇₈ R₂₇₉ R₂₈₀ R₂₈₁ R₂₈₂ ¹H NMR (CDCl₃) δppm 586 4-CF₃PhCO— —F —(CH₂)₂CH₃ —H —H 0.96 (3H, t, J = 7.3 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.63- 1.74 (2H, m), 3.32 (2H, t, J = 7.6 Hz), 4.01 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 6.35-6.47 (2H, m), 6.97 (1H, d, J = 7.8 Hz), 7.01 (1H, t, J = 8.9 Hz), 7.77 (2H, d, J = 8.2 Hz), 7.81 (1H, s), 7.99 (2H, d, J = 8.2 Hz), 8.19-8.22 (2H, m). 587 4-CF₃PhCO— —H —CH₃ —CH₃ —CH₃ 1.25 (3H, t, J = 7.1 Hz), 1.42 (6H, s), 2.91 (3H, s), 4.18 (2H, q, J = 7.1 Hz), 6.92 (1H, d, J = 8.7 Hz), 7.00 (2H, d, J = 9.2 Hz), 7.07 (2H, d, J = 9.1 Hz), 7.77 (2H, d, J = 8.2 Hz), 7.81 (1H, s), 8.00 (2H, d, J = 8.1 Hz), 8.20 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.28 (1H, d, J = 2.5 Hz). 588 3,4-Cl₂PhSO₂— —F —CH₃ —H —H 1.29 (3H, t, J = 7.1 Hz), 3.05 (3H, s), 4.03 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.38-6.49 (2H, m), 6.82 (1H, brs), 6.88 (1H, d, J = 8.7 Hz), 7.02 (1H, t, J = 8.8 Hz), 7.48 (1H, dd, J = 8.4, 1.6 Hz), 7.52 (1H, d, J = 8.4 Hz), 7.57 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.70 (1H, d, J = 2.6 Hz), 7.82 (1H, d, J = 1.8 Hz).

Reference Example 589 Production of ethyl 4-[5-(3,4-dimethylbenzoylamino)pyridin-2-yloxy]benzoate

To a solution of ethyl 4-(5-aminopyridin-2-yloxy)benzoate (14.15 g, 54.8 mmol) in DMF (100 mL) were added 3,4-dimethylbenzoic acid (8.23 g, 54.8 mmol), 1-hydroxybenzotriazole monohydrate (8.4 g, 54.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.6 g, 65.7 mmol) under ice cooling, and then stirred for 30 minutes under ice cooling and for 17 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added water (200 mL), and extracted with ethyl acetate (250 mL). The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 16.15 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=7.1 Hz), 2.33 (6H, s), 4.37 (2H, q, J=7.1 Hz), 6.99 (1H, d, J=9.7 Hz), 7.15 (2H, d, J=8.7 Hz), 7.24 (1H, d, J=7.7 Hz), 7.59 (1H, dd, J=7.7 Hz, 2.0 Hz), 7.65 (1H, d, J=2.0 Hz), 7.90 (1H, brs), 8.07 (2H, d, J=8.7 Hz), 8.25-8.35 (2H, m).

The following compounds were produced in the same manner as in Reference Example 589.

TABLE 83

Refer- ence Exam- ple No. R₂₈₃ R₂₈₄ R₂₈₅ ¹H NMR (CDCl₃) δppm 590 —Cl —Cl —Ac 2.58 (3H, s), 7.19 (1H, d, J = 8.7 Hz), 7.22 (2H, d, J = 8.7 Hz), 6.06 (2H, s), 7.84 (1H, d, J = 8.4 Hz), 7.97 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.01 (1H, d, J = 8.7 Hz), 8.24 (1H, d, J = 2.1 Hz), 8.28 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.56 (1H, d, J = 2.6 Hz), 10.64 (1H, brs). 591 —CN —H —COOCH₃ 3.92 (3H, s), 7.05 (1H, d, J = 8.9 Hz), 7.18 (2H, d, J = 8.6 Hz), 7.81 (2H, d, J = 8.6 Hz), 7.90 (1H, brs), 8.00 (2H, d, J = 8.6 Hz), 8.08 (2H, d, J = 8.6 Hz), 8.27 (1H, dd, J = 8.6 Hz, 2.6 Hz), 8.30 (1H, d, J = 2.3 Hz).

Reference Example 592 Production of ethyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]-3-ethoxyphenyl}propionate

To a solution of ethyl 3-[3-ethoxy-4-(5-nitropyridin-2-yloxy)phenyl]propionate (0.82 g, 2.3 mmol) in ethanol (40 mL) was added 10% palladium-carbon (0.15 g) under a nitrogen atmosphere, and the resulting solution was stirred under a hydrogen atmosphere at atmospheric pressure for 1 hour at room temperature. The palladium-carbon was removed by filtration, and the filtrate was concentrated. The obtained filtrate (0.58 g) was dissolved in dichloromethane (30 mL), and to the resulting solution were added pyridine (0.17 mL, 2.1 mmol) and 3,4-dichlorobenzoyl chloride (0.39 g, 1.84 mmol) under ice cooling. The resulting solution was stirred under ice cooling for 1 hour, and then stirred for 12 hours at room temperature. The reaction solution was made acidic by adding 10% hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 0.94 g of the title compound.

Appearance: Yellow amorphous powder

¹H NMR (CDCl₃) δ 1.18 (3H, t, J=7.0 Hz), 1.26 (3H, t, J=7.1 Hz), 2.53-2.71 (2H, m), 2.86-3.01 (2H, m), 3.98 (2H, q, J=7.0 Hz), 4.15 (2H, q, J=7.1 Hz), 6.78-6.88 (2H, m), 6.95 (1H, d, J=8.8 Hz), 7.06 (1H, d, J=7.9 Hz), 7.58 (1H, d, J=8.3 Hz), 7.65-7.77 (2H, m), 7.98 (1H, d, J=2.1 Hz), 8.14 (1H, dd, J=8.8 Hz, 2.7 Hz), 8.19 (1H, d, J=2.3 Hz).

The following compound was produced in the same manner as in Reference Example 592.

Reference Example 593 N-{6-[(4-(3-hydroxypropyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide

¹H NMR (CDCl₃) δ 1.86-1.97 (2H, m), 2.70-2.73 (2H, m), 3.68-3.73 (2H, m), 6.95 (1H, d, J=8.7 Hz), 7.03-7.08 (2H, m), 7.23 (2H, d, J=8.4 Hz), 7.77 (2H, d, J=8.2 Hz), 7.84 (1H, brs), 7.99 (2H, d, J=8.2 Hz), 8.20-8.23 (1H, m), 8.26 (1H, d, J=2.6 Hz).

Reference Example 594 Production of methyl 2-(4-{5-[3-(3,4-dichlorophenyl)ureido]pyridin-2-yloxy}phenyl]acetate

To a solution of methyl 2-[4-(5-aminopyridin-2-yloxy)phenyl]acetate (0.44 g, 1.7 mmol) in dichloromethane (7 mL) was added 3,4-dichlorophenylisocyanate (0.353 g, 1.9 mmol), and the resulting reaction solution was stirred for 1 hour at room temperature. To the reaction solution was added diisopropyl ether. Insoluble matter was removed by filtration, to thereby yield 0.60 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 3.63 (3H, s), 3.69 (2H, s), 6.99-7.05 (3H, m), 7.26-7.30 (2H, m), 7.35 (1H, dd, J=8.8, 2.4 Hz), 7.52 (1H, d, J=8.8 Hz), 7.86 (1H, d, J=2.4 Hz), 7.98 (1H, dd, J=8.8, 2.8 Hz), 8.18 (1H, d, J=2.7 Hz), 8.91 (1H, s), 9.10 (1H, s).

The following compounds were produced in the same manner as in Reference Example 594.

TABLE 84

Reference Example No. R₂₈₆ MS (M⁺) 595 —H 459 596 —CH₃ 473

TABLE 85

Reference Example No. R₂₈₇ ¹H NMR (CDCl₃) δppm or MS 597 4-CF₃Ph— ¹H NMR 1.18 (3H, t, J = 7.1 Hz), 1.25 (3H, t, J = 7.1 Hz), 2.62- 2.68 (2H, m), 2.96-3.01 (2H, m), 3.76 (2H, q, J = 7.1 Hz), 4.14 (2H, q, J = 7.1 Hz), 6.17 (1H, brs), 7.05 (1H, dd, J = 8.7 Hz, 0.7 Hz), 7.11 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 7.40 (2H, d, J = 8.7 Hz), 7.49 (2H, d, J = 8.6 Hz), 7.63 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.14 (1H, dd, J = 2.6 Hz, 0.7 Hz). 598 3,4-Cl₂Ph— MS 501 (M⁺)

TABLE 86

Reference Example No. R₂₈₈ M ¹H NMR (CDCl₃) δppm 599 —H 3 1.90-2.11 (2H, m), 2.28-2.50 (4H, m), 2.51-2.72 (2H, m), 2.82- 3.07 (2H, m), 3.28-3.51 (4H, m), 3.52-3.78 (4H, m), 5.25-5.40 (1H, m), 5.96 (2H, s), 6.69-6.81 (2H, m), 6.82-6.94 (2H, m), 6.95- 7.08 (2H, m), 7.09-7.26 (3H, m), 7.88-8.07 (2H, m). 600 —H 2 2.20-2.46 (4H, m), 2.52-2.70 (2H, m), 2.82-3.02 (2H, m), 3.28- 3.50 (4H, m), 3.51-3.72 (6H, m), 5.52-5.71 (1H, m), 5.95 (1H, s), 6.68-6.78 (2H, m), 6.80-6.89 (2H, m), 6.91 (2H, d, J = 8.4 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.36 (1H, s), 7.89-8.01 (2H, m). 601 —OCH₃ 3 1.85-2.08 (2H, m), 2.27-2.46 (4H, m), 2.55-2.71 (2H, m), 2.88- 3.03 (2H, m) 3.30-3.46 (6H, m), 3.56 (2H, t, J = 6.3 Hz), 3.63 (2H, t, J = 4.9 Hz), 3.71 (3H, s), 5.20-5.36 (1H, m), 5.95 (2H, s), 6.68- 6.89 (6H, m), 7.00 (1H, d, J = 8.0 Hz), 7.15 (1H, s), 7.87 (1H, d, J = 2.4 Hz), 7.92 (1H, dd, J = 2.8 Hz, 8.8 Hz). 602 —OCH₃ 2 2.25-2.49 (4H, m), 2.58-2.72 (2H, m), 2.87-3.05 (2H, m), 3.30- 3.71 (10H, m), 3.71 (3H, s), 5.40-5.52 (1H, m), 5.95 (2H, s), 6.66- 6.91 (6H, m), 7.00 (1H, d, J = 8.0 Hz), 7.07 (1H, s), 7.85-7.99 (2H, m).

TABLE 87 Reference Example No. Chemical Structure ¹H NMR (solvent) δppm 603

(DMSO-d₆) 3.38(2H, t, J = 6.1 Hz), 3.63(2H, t, J = 6.1 Hz), 3.68(3H, s), 6.27(1H, t, J = 6.1 Hz), 6.76-6.84(2H, m), 7.22- 7.31(2H, m), 8.41(1H, s). 604

(CDCl₃) 2.00-2.20(5H, m), 3.27- 3.47 (4H, m), 3.48-3.60(2H, m), 3.61-3.78 (2H, m), 3.88(3H, s), 3.89(3H, s), 4.59 (2H, s), 5.94- 6.12(1H, m), 6.66(1H, d, J = 8.8 Hz), 6.83(1H, d, J = 8.6 Hz), 6.80- 6.92(3H, m), 7.04(1H, dd, J = 2.6 Hz, 8.6 Hz), 7.19(1H, d, J = 2.6 Hz), 7.50(1H, d, J = 2.8 Hz, 8.8 Hz), 7.73(1H. s), 7.95(1H, d, J = 2.8 Hz). 605

(CDCl₃) 1.76-1.93(2H, m), 2.00- 2.20 (5H, m), 3.11-3.28(2H, m), 3.29-3.41 (2H, m), 3.42-3.57(2H, m), 3.60-3.78 (2H, m), 3.87(3H, s), 3.88(3H, s), 4.57 (2H, s), 5.70- 5.88(1H, m), 6.67(1H, d, J = 8.8 Hz), 6.83(1H, d, J = 8.6 Hz), 6.86(3H, m), 7.04(1H, dd, J = 2.6 Hz, 8.6 Hz), 7.17(1H, d, J = 2.6 Hz), 7.56(1H, dd, J = 2.8 Hz, 8.8 Hz), 7.68(1H, s), 7.93(1H, d, J = 2.8 Hz).

Reference Example 606 Production of methyl 3-(4-{5-[3-(4-trifluoromethylphenyl)ureido]pyridin-2-yloxy}phenyl)propionate

Methyl 3-[4-(5-nitropyridin-2-yloxy)phenyl]propionate (1.00 g, 3.3 mmol) was dissolved in a mixed solvent consisting of THF (1 mL) and ethanol (120 mL). To the resulting solution was added 10% palladium-carbon (100 mg), and stirred for 23 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated. To the residue were added THF (20 mL), triethylamine (0.917 mL, 6.6 mmol) and phenyl 4-trifluoromethylisocyanate (0.61 mL, 4.3 mmol), and the resulting solution was stirred for 20 hours at room temperature. The reaction solution was evaporated under reduced pressure. The residue was washed with ethyl acetate, to thereby yield 850 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.62-2.68 (2H, m), 2.83-2.68 (2H, m), 3.60 (3H, s), 6.97-7.02 (3H, m), 7.24 (2H, d, J=8.4 Hz), 7.65-7.69 (4H, m), 7.99 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.19 (1H, d, J=2.8 Hz), 8.88 (1H, s), 9.20 (1H, s).

Reference Example 607 Production of methyl 3-fluoro-4-{5-[(4-rifluoromethylbenzylidene)amino]pyridin-2-yloxy}benzoate

Methyl 4-(5-aminopyridin-2-yloxy)-3-fluorobenzoate (2.0 g, 7.63 mmol) was dissolved in methanol (50 mL). To the resulting solution was added 4-trifluoromethylbenzaldehyde (1.04 mL, 7.63 mmol), and refluxed for 6 hours. The reaction solution was cooled to room temperature, and the resulting precipitated crystals were collected by suction filtration. The collected crystals were washed with methanol, to thereby yield 2.81 g of the title compound.

Appearance: Pale grey powder

¹H NMR (DMSO-d₆) δ 3.89 (3H, s), 7.32 (1H, d, J=8.7 Hz), 7.48-7.54 (1H, m), 7.85-7.92 (4H, m), 8.01 (1H, dd, J=8.7 Hz, 2.6 Hz), 8.13-8.16 (3H, m), 8.86 (1H, s).

The following compounds were produced in the same manner as in Reference Example 607.

TABLE 88

Reference Example No. R₂₈₉ R₂₉₀ R₂₉₁ R₂₉₂ ¹H NMR (solvent) δppm 608 —CF₃ —H —H —CH₃ (DMSO-d₆) 3.86(3H, s), 7.24-7.30(3H, m), 7.92(2H, d, J = 8.1 Hz), 7.98-8.05(3H, m), 8.16(2H, d, J = 8.1 Hz), 8.24(1H, d, J = 2.1 Hz), 8.88(1H, s). 609 —CF₃ —H —H —C₂H₅ (DMSO-d₆) 1.33(3H, t, J = 7.1 Hz), 4.32(2H, q, J = 7.1 Hz), 7.24-7.30(3H, m), 7.92(2H, d, J = 8.3 Hz), 8.00(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.02(2H, d, J = 8.7 Hz), 8.16(2H, d, J = 7.9 Hz) 8.24(1H, d, J = 2.6 Hz), 8.88(1H, s). 610 —Cl —Cl —F —CH₃ (DMSO-d₆) 3.89(3H, s), 7.21(1H, d, J = 8.6 Hz), 7.48-7.54 (1H, m), 7.80-7.94(4H, m), 7.97(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.12- 8.15(2H, m), 8.75(1H, s). 611 —Cl —Cl —F —C₂H₅ (CDCl₃) 1.40(3H, t, J = 7.1 Hz), 4.39(2H, q, J = 7.1 Hz), 7.09(1H, d, J = 8.6 Hz), 7.26- 7.35(1H, m), 7.55-7.57(1H, m), 7.66-7.73(2H, m), 7.86-7.92(2H, m), 8.02-8.03(2H, m), 8.40(1H, s).

Reference Example 612 Production of ethyl 4-{5-[1-(4-trifluoromethylphenyl)ethylideneamino]pyridin-2-yloxy}benzoate

Ethyl 4-(5-aminopyridin-2-yloxy)benzoate (16.0 g, 62 mmol) was dissolved in toluene (300 mL). To the resulting solution were added 4-trifluoromethylacetophenone (11.7 g, 62 mmol) and (±)-camphor-10-sulfonic acid (1.08 g, 4.65 mmol), and refluxed overnight. The reaction solution was concentrated under reduced pressure, to thereby yield 26.5 g of the title compound.

Appearance: Dark green oil

¹H NMR (CDCl₃) δ 1.35-1.41 (3H, m), 2.34 (3H, s), 4.36 (2H, d, J=7.1 Hz), 7.01-7.31 (4H, m), 7.70-7.77 (3H, m), 8.01-8.11 (4H, m).

Reference Example 613 Production of methyl 4-[5-(4-trifluoromethylbenzylamino)pyridin-2-yloxy]benzoate

Methyl 4-{5-[(4-trifluoromethylbenzylidene)amino]pyridin-2-yloxy}benzoate (2.64 g, 6.59 mmol) was suspended in methanol (25 mL), and to the resulting suspension was slowly added sodium borohydride (1.25 g, 33.0 mmol). The resulting solution was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was washed with diethyl ether, to thereby yield 2.65 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 3.89 (3H, s), 4.16 (1H, brs), 4.42 (2H, s), 6.84 (1H, d, J=8.7 Hz), 7.01 (1H, dd, J=8.6 Hz, 3.0 Hz), 7.05 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.4 Hz), 7.62 (2H, d, J=8.3 Hz), 7.67 (1H, d, J=3.1 Hz), 8.01 (2H, d, J=8.6 Hz).

The following compounds were produced in the same manner as in Reference Example 613.

TABLE 89

Reference Example No. R₂₉₃ R₂₉₄ R₂₉₅ R₂₉₆ R₂₉₇ ¹H NMR (CDCl₃) δppm 614 —CF₃ —H —H —H —C₂H₅ 1.37(3H, t, J = 7.1 Hz), 4.19(1H, brs), 4.35(2H, q, J = 7.1 Hz), 4,41(2H, brs), 6.83(1H, d, J = 8.7 Hz), 7.01(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.04(2H, d, J = 8.6 Hz), 7.48(2H, d, J = 8.1 Hz), 7.61(2H, d, J = 8.3 Hz), 7.66(1H, d, J = 3.0 Hz), 8.02(2H, d, J = 8.7 Hz). 615 —CF₃ —H —CH₃ —H —C₂H₅ 1.37(3H, t, J = 7.1 Hz), 1.56(3H, d, J = 6.8 Hz), 4.06(1H, brs), 4.34(2H, q, J = 7.1 Hz), 4.49(1H, q, J = 6.6 Hz), 6.75(1H, d, J = 8.7 Hz), 6.87(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.01(2H, d, J = 8.6 Hz), 7.47(2H, d, J = 8.1 Hz), 7.53(1H, d, J = 3.0 Hz), 7.60(2H, d, J = 8.3 Hz), 8.00(2H, d, J = 8.7 Hz). 616 —CF₃ —H —H —F —CH₃ 3.90(3H, s), 4.40(2H, brs), 6.89(1H, d, J = 8.1 Hz), 7.03(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.15-7.21(1H, m), 7.47(2H, d, J = 8.1 Hz), 7.55(1H, d, J = 3.0 Hz), 7.61(2H, d, J = 8.1 Hz), 7.80-7.84(2H, m). 617 —Cl —Cl —H —F —CH₃ 3.91(3H, s), 4.29(2H, brs), 6.88(1H, d, J = 8.7 Hz), 7.02(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.15-7.21(2H, m), 7.41(1H, d, J = 8.3 Hz), 7.46(1H, d, J = 2.0 Hz), 7.53(1H, d, J = 3.0 Hz), 7.81-7.84(2H, m).

Reference Example 618 Production of ethyl 3-{4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}propionate

A solution of 3,4-dichlorobenzaldehyde (1.28 g, 7.3 mmol) was added to a solution of ethyl 3-[4-(5-aminopyridin-2-yloxy)phenyl]propionate (2.1 g, 7.3 mmol) in ethanol (20 mL), and the resulting solution was stirred for 2 hours at 40° C. To the resulting reaction solution was added sodium borohydride (0.55 g, 15.7 mmol) under ice cooling, and stirred at the same temperature for 1 hour. To the solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 2.71 g of the title compound.

Appearance: Colorless oil

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7.1 Hz), 2.50-2.68 (2H, m), 2.81-3.01 (2H, m), 3.71-4.20 (3H, m), 4.28 (2H, s), 6.76 (1H, d, J=8.7 Hz), 6.88-7.02 (3H, m), 7.06-7.23 (3H, m), 7.41 (1H, d, J=8.2 Hz), 7.46 (1H, d, J=2.0 Hz), 7.60 (1H, d, J=3.0 Hz).

The following compounds were produced in the same manner as in Reference Example 618.

TABLE 90

Reference Example No. R₂₉₈ R₂₉₉ R₃₀₀ Xa₂₁ ¹H NMR (CDCl₃) δppm 619 —CF₃ —H —H —CH₂— 1.24(3H, t, J = 7.3Hz), 2.60(2H, t, J = 8.1 Hz), 2.92(2H, t, J = 8.1 Hz), 4.13(2H, q, J = 7.3 Hz), 4.39(2H, s), 6.76(1H, d, J = 8.7 Hz), 6.97(2H, d, J = 8.4 Hz), 6.98(1H, dd, J = 8.6 Hz, 3.1 Hz), 7.17(2H, d, J = 8.4 Hz), 7.47(2H, d, J = 8.1 Hz), 7.60(2H, d, J = 7.9 Hz), 7.61(1H, d, J = 3.1 Hz). 620 —Cl —Cl —OCH₃ —CH₂— 1.25(3H, t, J = 7.1 Hz), 2.65-2.74(2H, m), 2.94(2H, t, J = 8.2 Hz), 3.76(3H, s), 3.93(1H, brs), 4.14(2H, q, J = 7.1 Hz), 4.22-4.34(2H, m), 6.70-6.85(3H, m), 6.85-7.02(2H, m), 7.10-7.25(1H, m), 7.39 (1H, d, J = 8.2 Hz), 7.44(1H, d, J = 2.0 Hz), 7.53(1H, d, J = 2.7 Hz). 621 —CF₃ —H —OCH₃ —CH₂— 1.25(3H, t, J = 7.1 Hz), 2.52-2.68(2H, m), 2.81- 3.01(2H, m), 3.76 (3H, s), 3.93(1H, brs), 4.14(2H, q, J = 7.1 Hz), 4.30-4.40(2H, m), 6.72-6.84(3H, m), 6.96(1H, d, J = 8.0 Hz), 6.98(1H, dd, J = 8.0 Hz, 3.0 Hz), 7.40(2H, d, J = 8.0 Hz), 7.55(1H, d, J = 3.0 Hz), 7.59 (2H, d. J = 8.0 Hz). 622 —Cl —Cl —OC₂H₅ —CH₂— 1.18(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz), 2.52-2.69(2H, m), 2.82-3.00(2H, m), 3.81-4.02(3H, m), 4.14(2H, q, J = 7.1 Hz), 4.27 (2H, d, J = 4.7 Hz), 6.72-6.82(3H, m), 6.93-7.02(2H, m), 7.18 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.39(1H, d, J = 8.4 Hz), 7.45(1H, d, J = 2.0 Hz), 7.52(1H, d, J = 3.0 Hz). 623 —CF₃ —H —OC₂H₅ —CH₂— 1.18(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz), 2.51-2.72(2H, m), 2.83-3.01(2H, m), 3.87-4.06(3H, m), 4.16(2H, q, J = 7.1 Hz), 4.30-4.42(2H, m), 6.72- 6.83(3H, m), 6.94-7.02(2H, m), 7.46(2H, d, J = 8.1 Hz), 7.54(1H, d, J = 3.0 Hz), 7.59(2H, d, J = 8.1 Hz). 624 —Cl —Cl —F —CH₂— 1.12-1.35(3H, m), 2.50-2.74(2H, m), 2.93(2H, t, J = 7.7 Hz), 3.95 (1H, brs), 4.05-4.20(2H, m), 4.27 (2H, s), 6.82(1H, d, J = 8.4 Hz), 6.90-7.15(4H, m), 7.18(1H, dd, J = 8.4 Hz. 2.0 Hz), 7.35-7.60(3H, m). 625 —CF₃ —H —F —CH₂— 1.13-1.35(3H, m), 2.65-2.70(2H, m), 2.93(2H, t, J = 7.7 Hz), 4.01 (1H, brs), 4.05-4.23(2H, m), 4.37(2H, s), 6.82(1H, d, J = 8.8 Hz). 6.90-7.15(4H, m), 7.37-7.55(3H, m), 7.55-7.70(2H, m). 626 —Cl —Cl —H —N(Ac)— 1.27(3H, t, J = 7.1 Hz), 1.94(3H, s), 4.10(1H, brs), 4.19(2H, q, J = 7.1 Hz), 4.31(2H, s), 4.34(2H, s), 6.84(1H, d, J = 8.5 Hz), 7.00(1H, dd, J = 8.5 Hz, 3.0 Hz), 7.06(2H, d, J = 8.7 Hz), 7.20(1H, dd, J = 8.2 Hz, 2.2 Hz), 7.31(2H, d. J = 8.7 Hz), 7.42(1H, d, J = 8.2 Hz), 7.47(1H, d, J = 2.2 Hz), 7.62(1H, d, J = 3.0 Hz). 627 —CF₃ —H —H —N(Ac)— 1.27(3H, t, d = 7.1 Hz), 1.93(3H, s), 4.15(1H, brs), 4.18(2H, q, J = 7.1 Hz), 4.34(2H, s), 4.35-4.50(2H, m), 6.83(1H, d, J = 8.6 Hz), 7.01(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.06(2H, d, J = 8.9 Hz), 7.31(2H, d, J = 8.9 Hz), 7.48(2H, d, J = 8.1 Hz), 7.62(2H, d, J = 8.1 Hz), 7.64(1H, d, J = 3.6 Hz).

Reference Example 628 Production of ethyl 3-(4-{5-[benzyloxycarbonyl(2-methoxyethyl)amino]pyridin-2-yloxy}phenyl)propionate

Under a nitrogen atmosphere, to a solution of ethyl 3-[4-(5-benzyloxycarbonylaminopyridin-2-yloxy)phenyl]propionate (1.7 g, 4.0 mmol) in DMF (50 mL) was added 60% sodium hydride (0.19 g, 4.9 mmol) under ice cooling, and the resulting solution was stirred for 35 minutes at the same temperature. 2-Bromoethylmethyl ether (0.4 mL, 4.2 mmol) was added dropwise to the solution. The reaction solution was stirred for 2 hours under ice cooling, and then stirred for 2 days at room temperature. To the reaction solution was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 1.6 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7.1 Hz), 2.57-2.70 (2H, m), 2.89-3.02 (2H, m), 3.52 (2H, t, J=5.4 Hz), 3.79 (2H, t, J=5.4 Hz), 4.14 (2H, q, J=7.1 Hz), 5.14 (2H, brs), 6.87 (1H, d, J=8.7 Hz), 6.89-7.10 (2H, m), 7.11-7.41 (7H, m), 7.47-7.69 (1H, m), 8.10 (1H, brs).

The following compounds were produced in the same manner as in Reference Example 628.

Reference Example 629 Ethyl [(4-{5-[(3,4-dichlorophenyl)methylamino]pyridin-2-yloxy}-2-trifluoromethylphenyl)ethylamino]acetate

MS 541 (M⁺).

TABLE 91

Reference Example No. R₃₀₁ R₃₀₂ ¹H NMR (CDCl₃) δppm or MS 630 4-CF₃PhCH₂— —(CH2)₂OCH₃ ¹H NMR 1.24(3H, t, J = 7.1 Hz), 2.54- 2.67(2H, m), 2.76-2.98(2H, m), 4.13(2H, q, J = 7.1 Hz), 4.61(2H, s), 6.76(1H, d, J = 8.9 Hz), 6.93-7.01(2H, m), 7.07(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.12-7.20 (2H, m), 7.33(2H, d, J = 8.0 Hz), 7.56(2H, d, J = 8.0 Hz), 7.65 (1H, d, J = 2.9 Hz). 631 4-CF₃PhCH₂— —C₂H₅ ¹H NMR 1.09-1.32(6H, m), 2.53-2.66(2H, m), 2.84-2.98(2H, m), 3.45 (2H, q, J = 7.1 Hz), 4.13(2H, q, J = 7.1 Hz), 4.49(2H, s), 6.77 (1H, d, J = 8.5 Hz), 6.93-7.01(2H, m), 7.02- 7.09(1H, m), 7.12-7.20(2H, m), 7.11-7.39(2H, m), 7.53-7.61(2H, m), 7.66 (1H, d, J = 3.0 Hz). 632 PhCH₂OCO— —C₂H₅ ¹H NMR 1.15(3H, t, J = 7.1 Hz), 1.25(3H, t, J = 7.1 Hz), 2.54-2.71(2H, m), 2.83-3.04(2H, m), 3.69(2H, q, J = 7.1 Hz), 4.14(2H, q, J = 7.1 Hz), 5.14(2H, brs), 6.88(1H, d, J =8.7 Hz), 7.02-7.11(2H, m), 7.18-7.40(7H, m), 7.44- 7.59(1H, m), 7.98-8.08(1H, m). 633 4-CF₃PhCH₂— —SO₂CH₃ MS 522(M⁺) 634 3,4-Cl₂PhCH₂— —SO₂CH₃ MS 522(M⁺) 635 3,4-Cl₂Ph— —CH₃ MS 444(M⁺)

Reference Example 636 Production of ethyl 3-{4-[5-(2-methoxyethylamino)pyridin-2-yloxy]phenyl}propionate

To a solution of ethyl 3-(4-{5-[benzyloxycarbonyl(2-methoxyethyl)amino]pyridin-2-yloxy}phenyl]propionate (1.82 g, 3.8 mmol) in ethanol-ethyl acetate (10 mL-10 mL) was added under a nitrogen atmosphere 10% palladium-carbon (0.2 g), and the resulting solution was stirred for 3 hours under a hydrogen atmosphere at atmospheric pressure. The palladium-carbon was filtered off through Celite, and the filtrate was evaporated to yield 1.23 g of the title compound.

Appearance: Blue oil

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7.1 Hz), 2.55-2.68 (2H, m), 2.87-2.98 (2H, m), 3.20-3.31 (2H, m), 3.56-3.66 (2H, m), 4.13 (2H, q, J=7.1 Hz), 6.77 (1H, d, J=8.7 Hz), 6.93-7.01 (2H, m), 7.03 (1H, dd, J=8.7 Hz, 3.0 Hz), 7.13-7.22 (2H, m), 7.66 (1H, d, J=3.0 Hz).

The following compound was produced in the same manner as in Reference Example 636.

Reference Example 637 Ethyl 3-[4-(5-ethylaminopyridin-2-yloxy)phenyl]-propionate

¹H NMR (CDCl₃) δ 1.29-1.32 (6H, m), 2.55-2.67 (2H, m), 2.87-2.99 (2H, m), 3.14 (2H, q, J=7.1 Hz), 4.13 (2H, q, J=7.1 Hz), 6.77 (18, d, J=8.7 Hz), 6.89-7.02 (3H, m), 7.09-7.25 (3H, m), 7.63 (1H, d, J=3.0 Hz).

Reference Example 638 Production of ethyl 3-(3-methoxy-4-{5-[methyl-(4-trifluoromethylbenzyl)amino]pyridin-2-yloxy}phenyl]-propionate

To a solution of ethyl 3-{3-methoxy-4-[5-(4-trifluoromethylbenzylamino]pyridin-2-yloxy)phenyl}-propionate (0.8 g, 1.7 mmol) in methanol (15 mL) were added a 37% aqueous formaldehyde solution (0.38 mL, 5.1 mmol) and acetic acid (0.1 mL, 1.7 mmol). The reaction solution was stirred for 30 minutes at room temperature. After that, sodium cyanoborohydride (0.24 g, 3.4 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred under ice cooling for 40 minutes. To the reaction solution was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.62 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7.1 Hz), 2.52-2.70 (2H, m), 2.87-3.02 (5H, m), 3.77 (3H, s), 4.14 (2H, q, J=7.1 Hz), 4.40-4.50 (2H, m), 6.74-6.86 ((3H, m), 6.97 (1H, d, J=8.0 Hz), 7.11 (1H, dd, J=8.9 Hz, 3.2 Hz), 7.34 (2H, d, J=8.1 Hz), 7.57 (2H, d, J=8.1 Hz), 7.65 (1H, d, 3.2 Hz).

The following compounds were produced in the same manner as in Reference Example 638.

TABLE 92

Reference Example No. R₃₀₃ R₃₀₄ R₃₀₅ ¹H NMR (CDCl₃) δppm 639 —H —CH₃ —CH₃ 3.07(3H, s), 3.89(3H, s), 4.56(2H, s), 6.87(1H, d, J = 8.9 Hz), 7.06(2H, d, J = 8.6 Hz), 7.13(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.35(2H, d, J = 8.1 Hz), 7.60(2H, d, J = 8.3 Hz), 7.75(1H, d, J = 3.1 Hz), 8.02(2H, d, J = 8.6 Hz). 640 —H —C₂H₅ —C₂H₅ 1.24(3H, t, J = 7.1 Hz), 1.37(3H, t, J = 7.1 Hz), 3.49(2H, q, J = 7.1 Hz), 4.35(2H, q, J = 7.1 Hz), 4.53(2H, s), 6.84(1H, d, J = 8.9 Hz), 7.05(2H, d, J = 8.6 Hz), 7.06(1H, dd, J = 8.9 Hz, 3.1 Hz), 7.36(2H, d, J = 8.4 Hz), 7.58(2H, d, J = 8.3 Hz), 7.69(1H, d, J = 3.1 Hz), 8.02(2H, d, J = 8.6 Hz). 641 —CH₃ —CH₃ —C₂H₅ 1.38(3H, t, J = 7.1 Hz), 1.59(3H, d, J = 6.9 Hz), 2.74(3H, s), 4.36(2H, q, J = 7.1 Hz), 4.49(1H, q, J = 6.9 Hz), 6.89(1H, d, J = 8.9 Hz), 7.08 (2H, d, J = 8.9 Hz), 7.24(1H, dd, J = 8.9 Hz, 3.1 Hz), 7.43(2H, d, J = 8.6 Hz), 7.61(2H, d, J = 8.3 Hz), 7.84(1H, d, J = 3.1 Hz), 8.03(2H, d, J = 8.9 Hz).

TABLE 93

Reference Example No. R₃₀₆ R₃₀₇ Xa₂₂ ¹H NMR (CDCl₃) δppm 642 —CH₃ —H —CH₂— 1.24(3H, t, J = 7.1 Hz), 2.60(2H, t, J = 7.8 Hz), 2.92(2H, t, J = 7.8 Hz), 3.02(3H, s), 4.12(2H, q, J = 7.1 Hz), 4.51(2H, s), 6.79(1H, d, J = 8.9 Hz), 6.97(2H, d, J = 8.4 Hz), 7.10(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.17(2H, d, J = 8.3 Hz), 7.34(2H, d, J = 8.1 Hz), 7.58(2H, d, J = 8.3 Hz), 7.69(1H, d, J = 3.1 Hz). 643 —CH₃ —H —N(Ac)— 1.27(3H, t, J = 7.1 Hz), 1.94(3H, s), 3.06(3H, s), 4.18(2H, q, J = 7.1 Hz), 4.34(2H, s), 4.55(2H, s), 6.87(1H, d, J = 8.9 Hz), 7.07(2H, d, J = 8.7 Hz), 7.13(1H, dd, J = 8.9 Hz, 3.1 Hz), 7.31(2H, d, J = 8.7 Hz), 7.35(2H, d, J = 8.0 Hz), 7.59(2H, d, J = 8.0 Hz), 7.72(1H, d, J = 3.1 Hz). 644 —CH₃ —F —CH₂— 1.25(3H, t, J = 7.1 Hz), 2.55-2.70(2H, m), 2.93(2H, t, J = 7.9 Hz), 3.00(3H, s), 4.13(2H, q, J = 7.1 Hz), 4.49(2H, s), 6.86(1H, d, J = 8.9 Hz), 6.90-7.16(4H, m), 7.33(2H, d, J = 8.1 Hz), 7.57(2H, d, J = 8.1 Hz), 7.62(1H, d, J = 3.2 Hz). 645 —CH₃ —OC₂H₅ —CH₂— 1.19(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz), 2.50- 2.69(2H, m), 2.81-2.99(2H, m), 2.98(3H, s), 3.98(2H, q, J = 7.0 Hz), 4.14(2H, q, J = 7.1 Hz), 4.48(2H, s), 6.68-6.88(3H, m), 7.00(1H, d, J = 8.0 Hz), 7.11(1H, dd, J = 8.0 Hz, 3.0 Hz), 7.33(2H, d, J = 8.0 Hz), 7.56(2H, d, J = 8.0 Hz), 7.64(1H, d, J = 3.0 Hz). 646 —C₂H₅ —F —CH₂— 1.19(3H, t, J = 7.1 Hz), 1.10-1.35(3H, m), 2.50- 2.70(2H, m), 2.93 (2H, t, J = 8.0 Hz), 3.43(2H, q, J = 7.1 Hz), 4.02-4.22(2H, m), 4.47 (2H, s), 6.83(1H, d, J = 9.0 Hz), 6.88-7.15(4H, m), 7.34(2H, d, J = 8.0 Hz), 7.41-7.70(3H, m). 647 —C₂H₅ —OCH₃ —CH₂— 1.18(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz), 2.57- 2.68(2H, m), 2.88-2.99(2H, m), 3.42(2H, q, J = 7.0 Hz), 3.77(3H, s), 4.14(2H, q, J = 7.1 Hz), 4.42- 4.50(2H, m), 6.72-6.86((3H, m), 6.97(1H, d, J = 8.0 Hz), 7.05(1H, dd, J = 9.0 Hz, 3.2 Hz), 7.30-7.38(2H, m), 7.51-7.59 (2H, m), 7.60(1H, d, J = 3.2 Hz). 648 —C₂H₅ —OC₂H₅ —CH₂— 1.17(3H, t, J = 7.0 Hz), 1.18(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz), 2.55-2.69(2H, m), 2.84- 2.98(2H, m), 3.42(2H, q, J = 7.1 Hz), 3.97(2H, q, J = 7.0 Hz), 4.13(2H, q, J = 7.0 Hz), 4.46(2H, s), 6.71- 6.82(3H, m), 6.99(1H, d, J = 8.0 Hz), 7.05(1H, dd, J = 8.9 Hz, 3.1 Hz), 7.34(2H, d, J = 8.0 Hz), 7.55(2H, d, J = 8.0 Hz), 7.59(1H, d, J = 3.1 Hz).

TABLE 94

Reference Example No. R₃₀₈ R₃₀₉ Xa₂₃ ¹H NMR (CDCl₃) δppm 649 —CH₃ —H —N(Ac)— 1.27(3H, t, J = 7.1 Hz), 1.94(3H, s), 3.03(3H, s), 4.19(2H, q, J = 7.1 Hz), 4.34(2H, s), 4.43(2H, s), 6.87(1H, d, J = 9.0 Hz), 7.03-7.11(1H, m), 7.07(2H, d, J = 8.7 Hz), 7.13(1H, dd, J = 9.0 Hz, 3.1 Hz), 7.27-7.35(1H, m), 7.31(2H, d, J = 8.7 Hz), 7.40(1H, d, J = 8.2 Hz), 7.71(1H, d, J = 3.1 Hz). 650 —CH₃ —F —CH₂— 1.15-1.30(3H, m), 2.53-2.70(2H, m), 2.93(2H, t, J = 7.9 Hz), 2.97(3H, s), 4.02-4.20(2H, m), 4.37(2H, s), 6.86(1H, d, J = 8.9 Hz), 6.91-7.18(5H, m), 7.32(1H, d, J = 2.0 Hz), 7.38(1H, d, J = 8.2 Hz), 7.61(1H, d, J = 2.9 Hz). 651 —CH₃ —OCH₃ —CH₂— 1.25(3H, t, J = 7.1 Hz), 2.55-2.75(2H, m), 2.85- 3.05(2H, m), 2.95(3H, s), 3.77(3H, s), 4.14(2H, q, J = 7.1 Hz), 4.36(2H, s), 6.71-6.88(3H, m), 6.98(1H, d, J = 8.1 Hz), 7.00-7.15(2H, m), 7.32(1H, d, J = 2.0 Hz), 7.38(1H, d, J = 8.1 Hz), 7.64(1H, d, J = 3.1 Hz). 652 —CH₃ —OC₂H₅ —CH₂— 1.19(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz), 2.55-2.72(2H, m), 2.84-3.01(5H, m), 3.98(2H, q, J = 7.0 Hz), 4.14(2H, q, J = 7.1 Hz), 4.29-4.40(2H, m), 6.74-6.83(3H, m), 7.00(1H, d, J = 8.0 Hz), 7.06(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.10(1H, dd, J = 9.0 Hz, 3.2 Hz), 7.31(1H, d, J = 2.0 Hz), 7.37(1H, d, J = 8.2 Hz), 7.63(1H, d, J = 3.2 Hz). 653 —C₂H₅ —F —CH₂— 1.17(3H, t, J = 7.1 Hz), 1.20-1.30(3H, m), 2.50- 2.72(2H, m), 2.93(2H, t, J = 7.8 Hz), 3.40(2H, q, J = 7.1 Hz), 4.00-4.22(2H, m), 4.36(2H, s), 6.83(1H, d, J = 8.9 Hz), 6.85-7.15(5H, m), 728-7.32(1H, m), 7.37(1H, d, J = 8.2 Hz), 7.56(1H, d, J = 3.2 Hz). 654 —C₂H₅ —OCH₃ —CH₂— 1.16(3H, t, J = 7.1 Hz), 1.21-1.35(3H, m), 2.50- 2.75(2H, m), 2.82-3.05(2H, m), 3.39(2H, q, J = 7.1 Hz), 3.77(3H, s), 4.05-4.25 (2H, m), 4.35(2H, s), 6.68-6.88(3H, m), 6.90-7.00(1H, m), 7.00-7.11(2H, m), 7.31(1H, d, J = 2.0 Hz), 7.37(1H, d, J = 8.2 Hz), 7.59(1H, d, J = 3.0 Hz). 655 —C₂H₅ —OC₂H₅ —CH₂— 1.11-1.22(6H, m), 1.25(3H, t, J = 7.1 Hz), 2.56- 2.67(2H, m), 2.86-2.97(2H, m), 3.39(2H, q, J = 7.1 Hz), 3.97(2H, q, J = 7.0 Hz), 4.14(2H, q, J = 7.1 Hz), 4.34(2H, s), 6.73-6.82(3H, m), 6.99 (1H, d, J = 8.0 Hz), 7.02-7.10(2H, m), 7.32(1H, d, J = 1.9 Hz), 7.36(1H, d, J = 8.2 Hz), 7.58(1H, d, J = 3.1 Hz).

Reference Example 656 Production of ethyl 3-(4-(5-(3,4-dichlorophenylamino)pyridin-2-yloxy)phenyl)propionate

Triethylamine (1.2 mL, 8.4 mmol) was added to a suspension of ethyl 3-(4-(5-aminopyridin-2-yloxy)phenyl)propionate (1.2 g, 4.2 mmol), 3,4-dichlorophenylboronic acid (1.6 g, 8.4 mmol), anhydrous copper acetate (0.762 g, 4.2 mmol) and molecular sieves 4A (5 g) in dichloromethane (24 mL), and the resulting reaction solution was stirred overnight at room temperature. After the resulting solution was filtered through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 1.5 g of the title compound.

Appearance: Slightly brown solid

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7.1 Hz), 2.60-2.66 (2H, m), 2.93-2.99 (2H, m), 4.14 (2H, q, J=7.1 Hz), 5.52 (1H, brs), 6.71 (1H, dd, J=8.7 Hz, 2.7 Hz), 6.90 (1H, d, J=8.7 Hz), 6.97 (1H, d, J=2.7 Hz), 7.04-7.08 (2H, m), 7.21-7.26 (3H, m), 7.49 (1H, dd, 8.7 Hz, 2.9 Hz), 8.01 (1H, d, J=2.8 Hz).

The following compound was produced in the same manner as in Reference Example 656.

Reference Example 657 Ethyl ({4-[5-(3,4-dichlorophenylamino)pyridin-2-yloxy]-2-trifluoromethylphenyl}ethylamino)acetate

MS 527 (M⁺).

Reference Example 658 Production of ethyl 4-[3-(4-benzyloxy-3-methyl)phenyl-2-oxotetrahydropyrimidin-1-yl]benzoate

Under a nitrogen atmosphere, to a solution of 1-(4-benzyloxy-3-methyl)phenyltetrahydropyrimidin-2-one (0.5 g, 1.7 mmol) in dioxane (5 mL) were added copper (I) iodide (16 mg, 0.08 mmol) and N,N-dimethylglycine hydrochloride (47 mg, 0.34 mmol). The resulting solution was stirred for 5 minutes, and then ethyl 4-iodobenzoate (0.39 g, 1.4 mmol) and potassium (III) phosphate (1.04 g, 4.9 mmol) were added to the reaction mixture. The resulting solution was stirred for 20 hours at 100° C., after which the resulting solution was sprinkled with silica gel. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1→dichloromethane:methanol=40:1), to thereby yield 0.43 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 1.30 (3H, t, J=7.1 Hz), 2.08-2.22 (5H, m), 3.66 (2H, t, J=5.9 Hz), 3.81 (2H, t, J=5.9 Hz), 4.28 (2H, q, J=7.1 Hz), 5.10 (2H, s), 6.86-7.14 (3H, m), 7.26-7.51 (7H, m), 7.82-7.92 (2H, m).

Reference Example 659 Production of ethyl (E)-3-(3-methoxy-4-{5-[2-(4-trifluoromethylphenyl)vinyl]pyridin-2-yloxy}phenyl)propionate

To ethyl 3-[4-(5-bromopyridin-2-yloxy)-3-methoxyphenyl]propionate (610 mg, 1.6 mmol) were added 4-trifluoromethylstyrene (0.332 mL, 2.2 mmol), dichlorobis(benzonitrile)palladium (II) (33 mg, 0.082 mmol), N,N-dimethylglycine hydrochloride (17 mg, 0.16 mmol), sodium acetate (263 mg, 3.2 mmol) and N-methylpyrrolidone (5 mL) under an argon atmosphere. The resulting solution was stirred under an argon atmosphere for 17 hours at 130° C. To the reaction solution was added ethyl acetate and filtered. The filtrate was washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 500 mg of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.1 Hz), 2.64-2.69 (2H, m), 2.95-3.01 (2H, m), 3.76 (3H, s), 4.05 (2H, q, J=7.1 Hz), 6.71-6.88 (2H, m), 6.95 (1H, d, J=8.6 Hz), 6.98-7.08 (2H, m), 7.11 (1H, d, J=16.5 Hz), 7.56-7.63 (4H, m), 7.87-7.91 (1H, m), 8.23 (1H, d, J=2.3 Hz).

The following compound was produced in the same manner as in Reference Example 659.

Reference Example 660 Ethyl 3-(4-{5-[(E)-2-(3,4-dichlorophenyl)vinyl]pyridin-2-yloxy}-3-methoxyphenyl)propionate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7.1 Hz), 2.63-2.69 (2H, m), 2.94-3.00 (2H, m), 3.76 (3H, s), 4.15 (2H, q, J=7.1 Hz), 6.81-6.90 (3H, m), 6.93 (1H, d, J=8.6 Hz), 6.99 (1H, d, J=15.3 Hz), 7.06 (1H, d, J=9.1 Hz), 7.27-7.31 (1H, m), 7.40 (1H, d, J=8.2 Hz), 7.55 (1H, d, J=2.0 Hz), 7.82-7.86 (1H, m), 8.19 (1H, d, J=2.5 Hz).

Reference Example 661 Production of ethyl {4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]benzenesulfonyl}acetate

To a solution of ethyl {4-[(4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenylsulfanyl}-acetate (1.20 g, 2.43 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (1.45 g, 6.06 mmol) at 0° C. The resulting solution was stirred for 2 hours at room temperature. To the reaction solution was added methanol and stirred for some time. To the resulting solution was then added water, and extracted with dichloromethane. The dichloromethane layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 1.28 g of the title compound.

Appearance: Yellow amorphous powder

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7.1 Hz), 4.11 (2H, s), 4.16 (2H, q, J=7.1 Hz), 7.06 (2H, d, J=8.9 Hz), 7.19 (1H, t, J=8.7 Hz), 7.30 (1H, d, J=8.7 Hz), 7.59 (1H, d, J=8.3 Hz), 7.71 (1H, dd, J=2.0 Hz, 8.3 Hz), 7.75-7.85 (1H, m), 7.86-7.95 (3H, m), 7.98 (1H, d, J=2.0 Hz).

Reference Example 662 Production of methyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridine-2-sulfinyl]phenyl}propionate

To a solution of methyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-ylsulfanyl]phenyl}propionate (1.00 g, 2.17 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (0.620 g, 2.60 mmol) at 0° C. The resulting solution was stirred for 1 hour at 0° C. To the reaction solution was added methanol and stirred for some time. To the resulting solution was then added water, and extracted with dichloromethane. The dichloromethane layer was washed with water, a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was recrystallized from ethanol 3 times, to thereby yield 0.790 g of the title compound.

Appearance: White powder

Melting point: 164-166° C.

Reference Example 663 Production of methyl 3-{4-[5-(3,4-dichlor benzoylamino)pyridine-2-sulfonyl]phenyl}propionate

To a solution of methyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-ylsulfanyl]phenyl}-propionate (1.00 g, 2.17 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (1.29 g, 5.42 mmol) at 0° C. The resulting solution was stirred for 1.5 hours at 0° C. To the reaction solution was added methanol and stirred for some time. To the resulting solution was then added water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was recrystallized from ethanol, to thereby yield 0.890 g of the title compound.

Appearance: White powder

Melting point: 165-166° C.

Reference Example 664 Production of ethyl {4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]benzenesulphenyl}acetate

To a solution of ethyl {4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenylsulfanyl}acetate (0.800 g, 1.61 mmol) in methanol (20 mL) was added a 31% hydrogen peroxide solution (2.08 mL, 18.5 mmol). The resulting solution was refluxed for 16 hours. The reaction solution was cooled with ice, and the resulting precipitated solid was collected by filtration, to thereby yield 0.631 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 1.13 (3H, t, J=7.1 Hz), 3.90-4.10 (4H, m), 7.14 (2H, d, J=8.8 Hz), 7.34 (1H, t, J=9.0 Hz), 7.55-7.65 (1H, m), 7.72 (2H, d, J=8.8 Hz), 7.64 (1H, d, J=8.4 Hz), 7.90-8.00 (2H, m), 8.22 (1H, d, J=2.0 Hz), 10.63 (1H, s).

Reference Example 665 Production of ethyl 3-(4-{5-[(4-(trifluoromethyl)phenylcarbamoyl]pyridin-2-yloxy}phenyl)butyrate

To a suspension of 60% sodium hydride (0.133 g, 3.3 mmol) in THF (6 mL) was added dropwise triethylphosphono acetate (0.53 mL, 2.7 mmol) under ice cooling, and the resulting solution was stirred for 1 hour at room temperature. To the reaction solution was added a solution of 6-(4-acetylphenoxy)-N-[4-(trifluoromethyl)phenyl]nicotinamide (0.53 g, 1.3 mmol) in THF (6 mL), and the resulting solution was stirred for 10 hours at 60° C. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.57 g of the intermediate product ethyl 3-(4-{5-[4-(trifluoromethyl)phenylcarbamoyl]pyridin-2-yloxy}phenyl)-2-butenoate. 10% palladium-carbon (0.057 g) was suspended in a mixed solvent consisting of ethanol (8 mL) and dioxane (2 mL), and to this suspension was added ethyl 3-(4-{5-[4-(trifluoromethyl)phenylcarbamoyl]pyridin-2-yloxy}phenyl)-2-butenoate (0.57 g, 1.2 mmol). The resulting product was subjected to catalytic reduction at atmospheric pressure and room temperature. Once the absorption of hydrogen had stopped, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 0.56 g of the title compound.

Appearance: White solid

¹H NMR (CDCl₃) δ 1.21 (3H, t, J=7.1 Hz), 1.33 (3H, d, J=7.0 Hz), 2.51-2.67 (2H, m), 3.28-3.37 (1H, m), 4.10 (2H, J=7.1 Hz), 7.00 (1H, d, J=8.6 Hz), 7.07-7.12 (2H, m), 7.26-7.31 (2H, m), 7.60-7.65 (2H, m), 7.73-7.77 (2H, m), 7.81 (1H, brs), 8.21 (1H, dd, J=8.6, 2.6 Hz), 8.68 (1H, d, J=2.3 Hz).

The following compound was produced in the same manner as in Reference Example 665.

Reference Example 666 Ethyl 2-methyl-3-{4-[5-(4-trifluoromethylphenylcarbamoyl)pyridin-2-yloxy]phenyl}propionate

MS 472 (M⁺)

Reference Example 667 Production of 3,4-dichloro-N-{6-[4-(N-hydroxycarbamimidoylmethyl)phenoxy]pyridin-3-yl}benzamide

To a solution of 3,4-dichloro-N-[6-(4-cyanomethylphenoxy)pyridin-]-yl]benzamide (700 mg, 1.76 mmol) in ethanol (30 mL) were added water (2 mL), hydroxylamine (420 mg, 12.71 mmol) and potassium carbonate (1.76 g, 12.73 mmol). Under argon, the resulting solution was stirred under reflux for 4 hours. The resulting reaction solution was concentrated under reduced pressure. To the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1), to thereby yield 510 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 3.27 (2H, s), 5.41 (2H, brs), 7.03 (2H, d, J=8.4 Hz), 7.05 (1H, d, J=8.8 Hz), 7.31 (2H, d, J=8.4 Hz), 7.84 (1H, d, J=8.4 Hz), 7.94 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.18 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.46 (1H, d, J=2.6 Hz), 8.88 (1H, s), 10.53 (1H, s).

Reference Example 668 Production of 3,4-dichloro-N-{6-[4-(N-acetoxycarbamimidoylmethyl)phenoxy]pyridin-3-yl}benzamide

To a solution of 3,4-dichloro-N-{6-[4-(N-hydroxycarbamimidoylmethyl)phenoxy]pyridin-3-yl}benzamide (510 mg, 1.18 mmol) in dioxane (8 mL) was added potassium carbonate (163 mg, 1.18 mmol). While stirring under ice cooling, to the resulting solution was added dropwise acetyl chloride (0.084 mL, 1.18 mmol), and the resulting solution was stirred for 15 minutes at room temperature. To the reaction solution was added THF (10 mL), and then water, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated. The residue was washed with ethyl acetate to yield 340 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.05 (3H, s), 3.35 (2H, s), 6.43 (2H, brs), 7.06 (1H, d, J=9.0 Hz), 7.06 (2H, d, J=8.6 Hz), 7.36 (2H, d, J=8.6 Hz), 7.84 (1H, d, J=8.3 Hz), 7.94 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.18 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.22 (1H, d, J=2.0 Hz), 8.47 (1H, d, J=2.5 Hz), 10.54 (1H, s).

Reference Example 669 Production of 4-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}-4-oxobutyric acid

To a suspension consisting of 3,4-dichloro-3′-fluoro-4′-phenoxybenzanilide (5.05 g, 13.4 mmol) and succinic anhydride (1.48 g, 14.8 mmol) in 1,2-dichloroethane (25 mL) was added aluminum chloride (6.26 g, 47.0 mmol) under ice cooling, and the resulting mixture was stirred at the same temperature for 5 minutes, and then at room temperature for 1.5 hours. The resulting reaction solution was poured into ice water, and the resulting solid was collected by filtration. To the solid was added 50% aqueous acetone (200 mL), and the resulting solution was refluxed for 0.5 hours, then cooled. The obtained solid was collected by filtration, to thereby yield 6.30 g of the title compound.

Appearance: White powder

Melting point: 205-208° C.

Reference Example 670 Production of ethyl 3-{4-[hydroxy(5-nitro-2-pyridyl)methyl]phenyl}propionate

To a solution of ethyl 3-[4-(5-nitropyridine-2-carbonyl)phenyl]propionate (1.52 g, 4.63 mmol) in dichloromethane (15 mL) and ethanol (15 mL) was added sodium borohydride (0.175 g, 4.63 mmol) under ice cooling, and the resulting solution was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in water and ethyl acetate. To the solution was added acetic acid and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 0.264 g of the title compound.

Appearance: Brown powder

¹H NMR (CDCl₃) δ 1.19 (3H, t, J=7.2 Hz), 2.56 (2H, t, J=7.8 Hz), 2.91 (2H, t, J=7.8 Hz), 4.09 (2H, q, J=7.2 Hz), 4.35 (1H, brs), 5.84 (1H, s), 7.17 (2H, d, J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz), 7.46 (1H, d, J=8.7 Hz), 8.40 (1H, dd, J=8.7 Hz, 2.5 Hz), 9.36 (1H, d, J=2.5 Hz).

The following compound was produced in the same manner as in Reference Example 670.

Reference Example 671 t-Butyl 4-[(2-hydroxy-3-(4-hydroxyphenyl)propionyl]-piperazine-1-carboxylate

¹H NMR (CDCl₃) δ 1.47 (9H, s), 1.62 (1H, brs), 2.85 (2H, d, J=6.0 Hz), 3.00-3.80 (8H, m), 4.56 (1H, t, J=6.0 Hz), 5.35 (1H, brs), 6.74 (2H, d, J=8.4 Hz), 7.06 (2H, d, J=8.4 Hz).

Reference Example 672 Production of ethyl 3-(4-{5-[(bis(3,4-dichlorobenzoyl)amino]-2-pyridylmethyl}phenyl)propionate

To a suspension of 10% palladium-carbon (27 mg) in ethanol (5 mL) were added a solution of ethyl 3-{4-[hydroxy(5-nitro-2-pyridyl)methyl]phenyl}propionate (0.264 g, 0.799 mmol) and 0.5 M hydrogen chloride in ethanol (2 mL), and the resulting solution was subjected to catalytic reduction at atmospheric pressure at 50° C. Once the absorption of hydrogen had stopped, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was suspended in THF (5 mL), and triethylamine (0.267 mL, 2.40 mmol) was added. To the solution was added dropwise a solution of 3,4-dichlorobenzoyl chloride (0.255 g, 0.879 mmol) in THF (1 mL) under ice cooling, and stirred for 1 hour at the same temperature. To the resulting solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 0.177 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7.2 Hz), 2.56 (2H, t, J=7.8 Hz), 2.89 (2H, t, J=7.8 Hz), 4.09 (2H, q, J=7.2 Hz), 6.99 (1H, s), 7.17 (2H, d, J=8.2 Hz), 7.35 (2H, d, J=8.2 Hz), 7.42 (1H, d, J=8.6 Hz), 7.43-7.56 (2H, m), 7.63 (1H, dd, J=8.6 Hz, 2.1 Hz), 7.85-7.94 (2H, m), 8.15 (1H, d, J=2.0 Hz), 8.20-8.32 (2H, m), 8.57 (1H, d, J=2.5 Hz).

Reference Example 673 Production of ethyl 3-(4-(5-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)pyridin-2-yloxy)phenyl)propionate

To a solution of ethyl 3-(4-(3-bromo-5-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)pyridin-2-yloxy)phenyl)propionate (0.41 g, 0.7 mmol) in ethanol (10 mL) were added 10% palladium-carbon (0.041 g) and ammonium formate (0.226 g, 3.6 mmol), and the resulting solution was heated to reflux for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.28 g of the title compound.

Appearance: White solid

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7.1 Hz), 2.60-2.66 (2H, m), 2.93-2.99 (2H, m), 4.14 (2H, q, J=7.1 Hz), 6.95 (1H, d, J=8.8 Hz), 7.01-7.05 (2H, m), 7.20-7.26 (3H, m), 7.50-7.54 (3H, m), 8.03 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.59 (1H, d, J=2.6 Hz).

Reference Example 674 Production of 1-(4-methoxyphenyl)imidazolin-2-one

To a suspension of 1-(2-chloroethyl)-3-(4-methoxyphenyl)urea (7.0 g, 30.6 mmol) in t-butanol (120 mL) was added potassium t-butoxide (6.4 g, 57.0 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 10 minutes, and then potassium butoxide (3.0 g, 26.7 mmol) was added. This solution was stirred for 10 minutes, and then potassium t-butoxide (4.3 g, 38.3 mmol) was added. The resulting solution was stirred for 16 hours at room temperature. The pH was adjusted to between 2 and 3 with 10% hydrochloric acid, and the solvent was evaporated under reduced pressure. To the residue were added water (100 mL) and ethyl acetate (100 mL), and stirred for 1 hour at room temperature. Resulting precipitates were filtered, washed with diethyl ether, and then dried under reduced pressure, to thereby yield 5.1 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 3.29-3.44 (2H, m), 3.70 (3H, s), 3.71-3.88 (2H, m), 6.77 (1H, s), 6.81-6.95 (2H, m), 7.35-7.50 (2H, m).

The following compounds were produced in the same manner as in Reference Example 674.

Reference Example 675 1-(4-Benzyloxy-3-methylphenyl)tetrahydropyrimidin-2-one

¹H NMR (DMSO-d₆) δ 1.81-1.96 (2H, m), 2.16 (3H, s), 3.11-3.25 (2H, m), 3.51 (2H, t, J=5.6 Hz), 5.09 (2H, s), 6.42 (1H, s), 6.91 (1H, d, J=8.7 Hz), 6.98 (1H, dd, J=2.6 Hz, 8.7 Hz), 7.04 (111, d, J=2.6 Hz), 7.28-7.34 (1H, m), 7.36-7.41 (2H, m), 7.42-7.48 (2H, m).

TABLE 95

Reference Example No. R₃₁₀ M mp (° C.) or ¹H NMR (CDCl₃) δppm 676 —H 1 mp 162.0-163.0 677 —H 2 mp 179.0-180.0 678 —OCH₃ 1 ¹H NMR 2.29-2.45(4H, m), 2.59-2.69(2H, m), 2.91-3.04(2H, m), 3.34-3.47(4H, m), 3.53-3.69(4H, m), 3.75(3H, s), 3.85-3.96(2H, m), 4.58(1H, s), 5.95(2H, s), 6.69-6.78(2H, m), 6.79-6.89(3H, m), 6.91(1H, d, J = 9.0 Hz), 7.02(1H, d, J = 8.0 Hz), 7.99(1H, d, J = 2.9 Hz), 8.25(1H, dd, J = 2.9 Hz, 9.0 Hz). 679 —OCH₃ 2 mp 140.0-141.5

TABLE 96

Reference Example No. M ¹H NMR (CDCl₃) δppm 680 1 1.98-2.14(2H, m), 2.18(3H, s), 3.30(2H, d, J = 6.0 Hz), 3.51-3.66(2H, m), 3.67- 3.78(2H, m), 3.80-4.05(8H, m), 4.57(2H, s), 4.79(1H, s), 6.78-6.94(4H, m), 6.99(1H, d, J = 8.6 Hz), 7.13(1H, dd, J = 2.6 Hz, 8.6 Hz), 7.22(1H, d, J = 2.6 Hz), 8.05(1H, d, J = 2.9 Hz), 8.22(1H, dd, J = 2.9 Hz, 9.0 Hz). 681 2 1.91-2.15(4H, m), 2.18(3H, s), 3.18-3.36(2H, m), 3.37-3.51(2H, m), 3.58-3.78(2H, m), 3.88(3H, s), 3.88(3H, s), 4.56(2H, s), 4.89(1H, s), 6.76-6.94(4H, m), 7.00(1H, d, J = 8.7 Hz), 7.13(1H, dd, J = 2.6 Hz, 8.7 Hz), 7.23(1H, d, J = 2.6 Hz), 7.67(1H, dd, J = 2.8 Hz, 8.8 Hz), 8.08(1H, d, J = 2.8 Hz).

Reference Example 682 Production of 3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionic acid

To a solution of ethyl 3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionate (6.00 g, 13.1 mmol) in THF (60 mL) and ethanol (30 mL) were added 5 M aqueous sodium hydroxide (3.14 mL, 15.7 mmol) and water (30 mL) and the resulting solution was refluxed for 1 hour. The reaction solution was cooled with ice. To the reaction solution were added 5 M hydrochloric acid (4.0 mL, 20.0 mmol) and water (100 mL). The obtained solid was collected by filtration, and recrystallized from water-containing acetone, to thereby yield 5.60 g of the title compound.

Appearance: White powder

Melting point: 188-190° C.

The following compounds were produced in the same manner as in Reference Example 682.

TABLE 97

Reference Example No. R₃₁₁ ¹H NMR (solvent) δppm or MS 683

¹H NMR (CDCl₃) 1.51(3H, d, J= 7.1 Hz), 2.12(3H, s), 2.91 (3H, s), 4.49(1H, q, J = 7.1 Hz), 6.71- 6.75(2H, m), 6.95-7.00 (2H, m), 8.45(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04(1H, dd, J = 2.8 Hz, 0.5 Hz). 684

MS 300(M⁺) 685

¹H NMR (DMSO-d₆) 7.39(1H, td, J = 2.0 Hz, 8.9 Hz), 7.50 (1H, d, J = 9.0 Hz), 7.78(1H, td, J = 2.1 Hz, 8.9 Hz), 8.70(1H, dd, J = 2.8 Hz, 9.0 Hz), 9.04(1H, d, J = 2.8 Hz), 11.35-11.91 (1H, m). 686

¹H NMR (CDCl₃) 2.72-2.77(2H, m), 2.98-3.03(2H, m), 3.74(3H, s), 6.85-6.89(2H, m), 7.03(1H, d, J = 9.1 Hz), 7.06-7.09(1H, m), 8.45(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01.(1H, d, J = 2.8 Hz). 687

¹H NMR (DMSO-d₆) 2.52(2H, t, J = 7.6 Hz), 2.80(2H, t, J = 7.6 Hz), 6.86(1H, d, J = 9.4 Hz), 7.21(2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 8.26(1H, dd, J = 2.9 Hz, 9.4 Hz), 9.01(1H, d, J = 2.9 Hz), 10.06(1H, s). 688

¹H NMR (DMSO-d₆) 2.96(3H, s), 4.09(2H, s), 6.44- 6.49 (2H, m), 6.56(1H, dd, J = 8.3 Hz, 2.4 Hz), 7.15(1H, d, J = 9.1 Hz), 7.20-7.26(1H, m), 8.59(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8 Hz). 689

¹H NMR (CDCl₃) 1.53(3H, d, J = 7.1 Hz), 2.93(3H, s), 4.51 (1H, q, J = 7.1 Hz), 6.87(2H, d, J = 9.2 Hz), 6.98(1H, d, J = 9.1 Hz), 7.05(2H, d, J = 9.1 Hz), 8.44(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, d, J = 2.6 Hz). 690

¹H NMR (CDCl₃) 2.63-2.69(2H, m), 2.97(3H, s), 3.68(2H, t, J = 7.1 Hz), 6.81(2H, d, J = 9.1 Hz), 6.98(1H, d, J = 9.1 Hz), 7.05(2H, d, J = 9.2 Hz), 8.44(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz). 691

¹H NMR (DMSO-d₆) 3.55(3H, s), 6.67(1H, d, J = 9.5 Hz), 7.52(2H, d, J = 8.5 Hz), 8.04(2H, d, J = 8.5 Hz), 8.21(1H, dd, J = 2.8 Hz, 9.5 Hz), 9.05(1H, d, J = 2.8 Hz), 13.10(1H, brs). 692

¹H NMR (DMSO-d₆) 1.28-1.32(2H, m), 1.75- 1.79(3H, m), 2.01(3H, s), 2.19(2H, d, J = 6.8 Hz), 2.65(2H, t, J = 12.0 Hz), 3.65(2H, d, J = 12.4 Hz), 6.80-6.96(3H, m), 7.15(1H, d, J = 9.2 Hz), 8.58(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01(1H, d, J = 2.8 Hz), 10.71(1H, brs). 693

MS 306(M⁺)

TABLE 98

Reference Example No. R₃₁₂ R₃₁₃ R₃₁₄ R₃₁₅ R₃₁₆ ¹H NMR (solvent) δppm 694 —F —H —H —H —CH₃ (CDCl₃) 3.09(3H, s), 4.12(2H, s), 6.45- 6.57(2H, m), 7.05-7.12(2H, m), 8.47(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02(1H, dd, J = 2.8 Hz, 0.7 Hz). 695 —F —H —H —H —C₂H₅ (CDCl₃) 1.25(3H, t, J = 7.1 Hz), 3.47(2H, q, J = 7.1 Hz), 4.06(2H, s), 6.42-6.53(2H, m), 7.04-7.10(2H, m), 8.47 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02(1H, dd, J = 2.8 Hz, 0.5 Hz). 696 —F —H —H —H allyl (CDCl₃) 4.03(2H, d, J = 5.0 Hz), 4.09(2H, s), 5.25-5.32 (2H, m), 5.82-5.96(1H, m), 6.44-6.56(2H, m), 7.04-7.10 (2H, m), 8.47(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02(1H, d, J = 2.6 Hz). 697 —F —H —H —F —CH₃ (DMSO-d₆) 2.94(3H, s), 4.04(3H, s), 6.92(1H, dd, J = 8.5 Hz, 12.9 Hz), 7.30(1H, dd, J = 7.5 Hz, 13.7 Hz), 7.35 (1H, d, J = 9.1 Hz), 8.63(1H, dd, J = 2.8 Hz, 9.1 Hz), 9.04(1H, d, J = 2.8 Hz), 12.41-12.82(1H, m). 698 —F —H —H —F —C₂H₅ (DMSO-d₆) 1.10(3H, t, J = 7.0 Hz), 3.12- 3.48(2H, m), 4.01(2H, s), 6.90(1H, dd, J = 8.4 Hz, 13.1 Hz), 7.29(1H, dd, J = 7.6 Hz, 13.7 Hz), 7.35(1H, d, J = 9.0 Hz), 8.63 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.04(1H, d, J = 2.8 Hz), 12.41-12.70(1H, m). 699 —F —H —F —H —CH₃ (DMSO-d₆) 2.96(3H, s), 4.26(2H, s), 6.41- 6.61(2H, m), 7.43(1H, d, J = 9.1 Hz), 8.65(1H, dd, J = 2.8 Hz, 9.1 Hz), 9.05(1H, d, J = 2.8 Hz), 12.56-12.90(1H, m). 700 —CH₃ —CH₃ —H —H —CH₃ (CDCl₃) 2.07(3H, s), 2.32(3H, s), 2.85(3H, s), 3.76(2H, s), 6.91(1H, d, J = 8.7 Hz), 7.00(1H, dd, J = 9.1 Hz, 0.6 Hz), 7.09(1H, d, J = 8.7 Hz), 8.46(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04(1H, dd, J = 2.8 Hz, 0.6 Hz). 701 —CH₃ —H —H —CH₃ —C₂H₅ (DMSO-d₆) 0.98(3H, t, J =7.1 Hz), 1.98(3H, s), 2.20 (3H, s), 3.09(2H, q, J = 7.1 Hz), 3.70(2H, s), 6.91(1H, s), 7.06(1H, s), 7.18(1H, d, J = 9.1 Hz), 8.59(1H, dd, J = 9.1 Hz, 2.9 Hz), 9.03(1H, d, J = 2.9 Hz), 12.30(1H, brs). 702 —H —H —H —H —SO₂CH₃ (DMSO-d₆) 3.17(3H, s), 4.43(2H, s), 7.29(2H, d, J = 8.7 Hz), 7.31(1H, d, J = 9.1 Hz), 7.55(2H, d, J = 8.9 Hz), 8.64(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, d, J = 2.8 Hz). 703 —CH₃ —H —H —H —SO₂CH₃ (DMSO-d₆) 2.09(3H, s), 3.11(3H, s), 4.42(2H, s), 7.20(1H, d, J = 8.6 Hz), 7.31(1H, d, J = 9.1 Hz), 7.37(1H, dd, J = 8.6 Hz, 2.5 Hz), 7.44(1H, d, J = 2.3 Hz), 8.64(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03(1H, d, J = 2.8 Hz), 12.88(1H, brs).

TABLE 99

Reference Example No. R₃₁₇ R₃₁₈ R₃₁₉ R₃₂₀ R₃₂₁ R₃₂₂ ¹H NMR (solvent) δppm or MS 704 —NO₂ —H —CH₃ —H —CH₃ —CH₃ MS 331(M⁺) 705 —NO₂ —H —CF₃ —H —H —CH₃ MS 371(M⁺) 706 —NO₂ —H —CF₃ —H —H —C₂H₅ MS 385(M⁺) 707 —NO₂ —CH₃ —H —CF₃ —H —CH₃ MS 385(M⁺) 708 —NO₂ —H —F —F —H —CH₃ ¹H NMR (DMSO-d₆) 2.98(3H, s), 4.05 (2H, s), 6.64-6.88(1H, m), 6.96-7.20 (1H, m), 7.38(1H, d, J = 9.1 Hz), 8.64 (1H, dd, J = 2.7 Hz, 9.1 Hz), 9.04(1H, d, J = 2.7 Hz), 12.24-12.95(1H, m). 709 —NO₂ —H —OCH₃ —H —H —SO₂CH₃ ¹H NMR (DMSO-d₆) 3.16(3H, s), 3.70 (3H, s), 4.45(2H, s), 7.10-7.30(4H, m), 8.61(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02 (1H, d, J = 2.8 Hz), 12.97(1H, brs). 710 —Br —H —F —H —F —CH₃ ¹H NMR (DMSO-d₆) 2.92(3H, s), 4.01 (2H, s), 6.80-6.93(1H, m), 7.11(1H, d, J = 8.8 Hz), 7.14-7.26(1H, m), 8.06 (1H, dd, J = 2.6 Hz, 8.8 Hz), 8.25(1H, d, J = 2.6 Hz), 12.18-12.89(1H, m). 711 4-CF₃PhCH₂— —H —H —H —H —CH₃ ¹H NMR (CDCl₃) 3.04(3H, s), 3.93(2H, s), 4.04(2H, s), 6.69(2H, d, J = 9.1 Hz), 6.70(1H, d, J = 8.5 Hz), 6.97(2H, d, J = 9.1 Hz), 7.25(2H, d, J = 8.6 Hz), 7.39(1H, dd, J = 8.5 Hz, 2.5 Hz), 7.52(2H, d, J = 8.6 Hz), 8.09(1H, d, J = 2.5 Hz), 11.26(1H, brs). 712 4-CF₃PhOCH₂— —H —H —H —H —SO₂CH₃ ¹H NMR (DMSO-d6) 3.11(3H, s), 4.40(2H, s), 5.18(2H, s), 7.12(1H, d, J = 8.9 Hz), 7.15-7.23(4H, m), 7.49(2H, d, J = 8.9 Hz), 7.67(2H, d, J = 8.6 Hz), 7.98(1H, dd, J = 8.4 Hz, 2.5 Hz), 8.28 (1H, d, J = 2.0 Hz), 12.41(1H, brs). 713 4-CF₃PhOCH₂— —H —CH₃ —H —H —SO₂CH₃ ¹H NMR (DMSO-d6) 2.06(3H, s), 3.18 (3H, s), 3.89(2H, s), 5.15(2H, s), 7.02 (1H, d, J = 8.4 Hz), 7.07(1H, d, J = 8.6 Hz), 7.21(2H, d, J = 8.4 Hz), 7.44(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.49(1H, d, J = 2.3 Hz), 7.67(2H, d, J = 8.9 Hz), 7.95 (1H, dd, J = 8.4 Hz, 2.5 Hz), 8.24(1H, d, J = 2.5 Hz).

TABLE 100

Reference Example No. R₃₂₃ R₃₂₄ ¹H NMR (solvent) δppm 714 —H —H (DMSO-d₆) 3.35(1H, brs), 3.84(2H, s), 6.63(2H, d, J = 8.9 Hz), 6.96(2H, d, J = 8.9 Hz), 7.14(1H, d, J = 9.1 Hz), 8.59(1H, dd, J = 2.9 Hz, 9.1 Hz), 9.05(1H, d, J = 2.9 Hz). 715 —H —CH₃ (CDCl₃) 3.09(3H, s), 4.11(2H, s), 6.74(2H, d, J = 9.1 Hz), 6.97(1H, dd, J = 9.1 Hz, 0.5 Hz), 7.04(2H, d, J = 9.1 Hz), 8.43(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04(1H, dd, J = 2.8 Hz, 0.5 Hz). 716 —H —C₂H₅ (CDCl₃) 1.24(3H, t, J = 7.1 Hz), 3.48(2H, q, J = 7.1 Hz), 4.07(2H, s), 6.73(2H, d, J = 9.2 Hz), 6.98(1H, d, J = 9.1 Hz), 7.04(2H, d, J = 9.2 Hz), 8.44(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, d, J = 2.8 Hz). 717 —OCH₃ —H (DMSO-d₆) 3.62(3H, s), 3.83(2H, s), 6.13(1H, dd, J = 8.6 Hz, 2.5 Hz), 6.41(1H, d, J = 2.5 Hz), 6.90(1H, d, J = 8.6 Hz), 7.09(1H, d, J = 8.6 Hz), 8.54(1H, dd, J = 9.1 Hz, 3.0 Hz), 9.00(1H, d, J = 3.0 Hz). 718 —OCH₃ —CH₃ (DMSO-d₆) 3.00(3H, s), 3.65(3H, s), 4.12(2H, s), 6.21(1H, dd, J = 8.8 Hz, 2.8 Hz), 6.39(1H, d, J = 2.8 Hz), 6.96(1H, d, J = 8.8 Hz), 7.11(1H, d, J = 9.1 Hz), 8.54(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.00(1H, d, J = 2.8 Hz), 12.57(1H, s). 719 —OCH₃ —C₂H₅ (DMSO-d₆) 1.13(3H, t, J = 7.0 Hz), 3.42(2H, q, J = 7.0 Hz), 3.64(3H, s), 4.05(2H, s), 6.14(1H, dd, J = 8.8 Hz, 2.8 Hz), 6.31(1H, d, J = 2.8 Hz), 6.95(1H, d, J = 8.8 Hz), 7.12(1H, d, J = 9.1 Hz), 8.53(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.00(1H, d, J = 2.8 Hz), 12.59(1H, brs). 720 —CH₃ —Ac (DMSO-d₆) 1.86(3H, s), 2.08(3H, s), 4.26(2H, s), 7.05-7.50(4H, m), 8.63 (1H, dd, J = 9.1 Hz, 2.9 Hz), 9.02(1H, dd, J = 2.9 Hz, 0.4 Hz), 12.72(1H, brs). 721 —CH₃ —H (CDCl₃) 2.09(3H, s), 3.98(2H, s), 5.26(1H, brs), 6.50-6.55(2H, m), 6.92(1H, d, J = 8.4 Hz), 6.98(1H, d, J = 8.1 Hz), 8.45(1H, dd, J = 8.1 Hz, 2.8 Hz), 9.04(1H, d, J = 2.8 Hz). 722 —CH₃ —CH₃ (DMSO-d₆) 1.99(3H, s), 2.97(3H, s), 4.09(2H, s), 6.52(1H, dd, J = 8.8 Hz, 3.0 Hz), 6.59(1H, d, J = 3.0 Hz), 6.92(1H, d, J = 8.8 Hz), 7.13(1H, dd, J = 9.1 Hz, 0.3 Hz), 8.57(1H, dd, J = 9.1 Hz, 2.9 Hz), 9.01(1H, d, J = 2.9 Hz), 12.54(1H, brs). 723 —CH₃ —C₂H₅ (DMSO-d₆) 1.11(3H, t, J = 7.0 Hz), 1.98(3H, s), 3.89(2H, q, J = 7.0 Hz), 4.02(2H, s), 6.44(1H, dd, J = 8.8 Hz, 2.9 Hz), 6.51(1H, d, J = 2.9 Hz), 6.90(1H, d, J = 8.8 Hz), 7.13(1H, d, J = 9.1 Hz), 8.56(1H, dd, J = 9.1 Hz, 2.9 Hz), 9.01(1H, d, J = 2.9 Hz), 12.53(1H, brs). 724 —CH₃

(DMSO-d₆) 0.54-0.59(2H, m), 0.80-0.87(2H, m), 2.02(3H, s), 2.64-2.71 (1H, m), 4.11(2H, s), 6.77-6.81(1H, m), 6.85(1H, d, J = 2.8 Hz), 6.96(1H, d, J = 8.7 Hz), 7.17(1H, dd, J = 9.2 Hz, 0.5 Hz), 8.59(1H, dd, J = 9.1 Hz, 3.0 Hz), 9.04(1H, dd, J = 3.0 Hz, 0.5 Hz), 12.56(1H, brs). 725 —F —H (DMSO-d₆) 3.82(2H, s), 6.43(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.53(1H, dd, J = 13.4 Hz, 2.6 Hz), 7.07(1H, t, J = 8.9 Hz), 7.28(1H, dd, J = 9.1 Hz, 0.5 Hz), 8.61(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03(1H, dd, J = 2.8 Hz, 0.5 Hz).

TABLE 101

Reference Example No. R₃₂₅ R₃₂₆ mp (° C.) or ¹H NMR (solvent) δppm 726 4-NO₂Ph— 4-N(CH₃)CH₂COOH ¹H NMR (CDCl₃) 3.10(3H, s), 4.13(2H, s), 6.74(2H, d, J = 9.2 Hz), 6.95(2H, d, J = 9.2 Hz), 7.00(2H, d, J = 9.2 Hz), 8.17(2H, d, J = 9.2 Hz). 727

2-(CH₂)₂COOH mp 157-159 728

3-(CH₂)₂COOH mp 192-194 729

4-(CH₂)₂COOH ¹H NMR (CDCl₃) 2.67(2H, t, J = 7.7 Hz), 2.94(2H, t, J = 7.7 Hz), 6.78 (1H, dd, J = 8.2 Hz, 1.2 Hz), 6.97(2H, d, J = 8.6 Hz), 7.02- 7.19(2H, m), 7.20(2H, d, J = 8.6 Hz), 7.48(1H, d, J = 8.3 Hz), 7.56(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.84(1H, d, J = 2.1 Hz), 8.38(1H, brs), 8.49(1H, dd, J = 8.3 Hz, 2.1 Hz), 10.46(1H, brs). 730

4-(CH₂)₂COOH ¹H NMR (CDCl₃) 2.67(2H, t, J = 7.6 Hz), 2.93(2H, t, J = 7.6 Hz), 6.78 (1H, dt, J = 8.1 Hz, 1.2 Hz), 6.95(2H, d, J = 8.5 Hz), 7.16(2H, d, J = 8.5Hz), 7.22-7.34(3H, m), 7.53(1H, d, J = 8.3 Hz), 7.64(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.73(1H, brs), 7.90(1H, d, J = 2.1 Hz), 10.23(1H, brs). 731

4-(CH₂)₂COOH ¹H NMR (DMSO-d₆) 1.05(3H, t, J = 7.1 Hz), 2.56(2H, t, J = 7.6 Hz), 2.84(2H, t, J = 7.6 Hz), 3.64 (2H, q, J = 7.1 Hz), 7.05-7.10(3H, m), 7.28(2H, d, J = 8.6 Hz), 7.45(2H, brs), 7.76-7.80(2H, m), 8.08 (1H, dd, J = 2.8 Hz, 0.5 Hz), 8.27(1H, brs), 12.10(1H, brs). 732

4-(CH₂)₂COOH ¹H NMR (DMSO-d₆) 1.06(3H, t, J = 7.1 Hz), 2.53-2.59(2H, m), 2.81-2.87(2H, m), 3.67(2H, q, J = 7.1 Hz), 7.05-7.10(3H, m), 7.29(2H, d, J = 8.7 Hz), 7.56(2H, d, J = 8.7 Hz), 7.66(2H, d, J = 8.7 Hz), 7.78(1H, dd, J = 8.6 Hz, 2.8 Hz), 8.09(1H, d, J = 2.8 Hz), 8.41(1H, brs), 12.14(1H, brs).

TABLE 102

Reference Example No. R₃₂₇ Xa₂₄ M Form mp (° C.) of ¹H NMR (DMSO-d₆) δppm 733 —H none 0 free mp 252-255 734 —F none 0 free mp 257-259 735 —F none 1 free mp 204-206 736 —F none 2 free mp 173-174 737 —F none 3 free mp 175-177 738 —F —S— 1 Na ¹H NMR 3.86(2H, s), 6.86(2H, d, J = 8.7 Hz), salt 7.15(1H, t, J = 9.0 Hz), 7.25(2H, d, J = 8.7 Hz), 7.55(1H, d, J = 9.0 Hz), 7.80(1H, d, J = 8.4 Hz), 7.91(1H, dd, J = 2.4 Hz, 13.3 Hz), 7.98(1H, dd, J = 2.0 Hz, 8.4 Hz), 8.25(1H, d, J = 2.0 Hz). 739 —F —SO— 1 free ¹H NMR 3.79(1H, d, J = 14.3 Hz), 3.97(1H, d, J = 14.3 Hz), 7.12(2H, d, J = 8.8 Hz), 7.33(1H, t, J = 9.1 Hz), 7.55-7.65(1H, m), 7.71(2H, d, J = 8.8 Hz), 7.84(1H, d, J = 8.4 Hz), 7.90-7.95(2H, m), 8.20(1H, d, J = 2.0 Hz), 10.63(1H, s), 13.20(1H, brs). 740 —F —SO₂— 1 free mp 214-216 741 —F —N(Ac)— 1 free ¹H NMR 1.80(3H, s), 4.22(2H, s), 7.00(1H, d, J = 8.9 Hz), 7.25-7.30(1H, m), 7.38(2H, d, J = 8.9 Hz), 7.50-7.60(1H, m), 7.84(1H, d, J = 8.4 Hz), 7.90-7.96(2H, m), 8.21(1H, d, J = 2.0 Hz), 10.61(1H, s), 12.68(1H, s). 742 —F

0 free mp 241-243 (—SO— means a group of

and —SO₂— means a group of

Hereinafter —SO— and —SO₂— indicate the same meanings.)

TABLE 103

Reference Example No. R₃₂₈ R₃₂₉ Xa₂₅ M mp (° C.) or ¹H NMR (DMSO-d₆) δppm 743 —Cl —Cl —CO— 2 ¹H NMR 2.60(2H, t, J = 7.6 Hz), 2.91 (2H, t, J = 7.6 Hz), 7.39(2H, d, J = 8.2 Hz), 7.82- 8.20(4H, m), 8.07(1H, d, J = 8.6 Hz), 8.25(1H, dd, J = 7.5 Hz, 2.1 Hz), 8.45(1H, dd, J = 8.6 Hz, 2.5 Hz), 9.03(1H, d, J = 2.5 Hz), 10.91(1H, s), 12.16(1H, brs). 744 —Cl —Cl —S— 2 mp 201-202 745 —Cl —Cl —SO— 2 mp 202-205 746 —Cl —Cl —SO₂— 2 mp 172-173 747 —Cl —Cl —NH— 2 ¹H NMR 2.76(2H, t, J = 7.6 Hz), 3.20-3.40 (2H, m), 6.86(1H, d, J = 8.8 Hz), 7.12(2H, d, J = 8.3 Hz), 7.52(2H, d, J = 8.3 Hz), 7.83(1H, d, J = 8.4 Hz), 7.90-7.96(2H, m), 8.21(1H, d, J = 1.3 Hz), 8.45(1H, d, J = 2.4 Hz), 9.03(1H, brs), 10.37(1H, s), 12.11(1H, brs). 748 —Cl —Cl —N(CH₃)— 2 mp 158-160 749 —CF₃ —H —N(CH₃)— 0 mp 240-243 750 —CF₃ —H —N(CH₃)— 2 ¹H NMR 2.57(2H, t, J = 7.5 Hz), 2.84(2H, t, J = 7.5 Hz), 3.38(3H, s), 6.61(1H, d, J = 9.1 Hz), 7.22(2H, d, J = 8.3 Hz), 7.29(2H, d, J = 8.3 Hz), 7.80-7.85(1H, m), 7.91(2H, d, J = 8.3 Hz), 8.15(2H, d, J = 8.3 Hz), 8.51(1H, d, J = 2.5 Hz), 10.42(1H, s), 12.10(1H, brs). 751 —Cl —Cl —N(CH₂Ph)— 2 ¹H NMR 2.53(2H, t, J = 7.9 Hz), 2.80(2H, t, J = 7.9 Hz), 5.21(2H, s), 6.63(1H, d, J = 9.1 Hz), 7.15-7.30 (9H, m), 7.75-7.95(3H, m), 8.19(1H, d, J = 2.1 Hz), 8.45(1H, d, J = 2.5 Hz), 10.34(1H, s), 12.10(1H, brs).

TABLE 104

Reference Example No. R₃₃₀ R₃₃₁ R₃₃₂ M mp (° C.) or ¹H NMR (DMSO-d₆) δppm 752 —H —CN —H 0 ¹H NMR 7.18-7.21(3H, m), 7.98(2H, d, J = 8.2 Hz), 8.05(2H, d, J = 8.9 Hz), 8.13(2H, d, J = 8.2 Hz), 8.28(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.57(1H, d, J = 2.6 Hz), 10.70(1H, s), 12.87(1H, brs). 753 —Cl —Cl —H 0 ¹H NMR 7.17-7.22(3H, m), 7.85(1H, d, J = 8.2 Hz), 7.94-8.01(3H, m), 8.23-8.29(2H, m), 8.55(1H, d, J = 2.6 Hz), 10.01(1H, s), 12.87 (1H, brs). 754 —H —Cl —H 0 ¹H NMR 7.16-7.21(3H, m), 7.63(2H, d, J = 8.6 Hz), 7.97-8.02(4H, m), 8.28(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.57(1H, d, J = 2.6 Hz), 10.53(1H, s), 12.86(1H, brs). 755 —H —CF₃ —H 0 ¹H NMR 7.18-7.22(3H, m), 7.93-8.00(4H, m), 8.18(2H, d, J = 8.4 Hz), 8.30(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.58(1H, d, J = 2.7 Hz), 10.69(1H, s), 12.91(1H, brs). 756 —CH₃ —CH₃ —H 0 ¹H NMR 2.30(3H, s), 2.31(3H, s)(, 7.16(1H, d, J = 8.9 Hz), 7.18(2H, d, J = 8.7 Hz), 7.31(1H, d, J = 7.6 Hz), 7.72(1H, d, J = 7.6 Hz), 7.77 (1H, s), 7.98(2H, d, J = 8.7 Hz), 8.28(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.58(1H, d, J = 2.7 Hz), 10.35(1H, s), 12.88(1H, brs). 757 —CF₃ —H —F 0 mp 238-239 758 —OCF₃ —H —H 0 ¹H NMR 7.18-7.22(3H, m), 7.61-7.81(2H, m), 7.89- 8.06(4H, m), 8.28(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.57(1H, d, J = 2.3 Hz), 10.62(1H, s), 12.95(1H, brs). 759 —CF₃ —H —H 0 ¹H NMR 7.11-7.22(3H, m), 7.70-7.85(1H, m), 7.90- 8.05(3H, m), 8.2-8.35(3H, m), 8.6(1H, d, J = 2.4 Hz), 10.70(1H, s), 12.90(1H, brs). 760 —H —CF₃ —H 1 ¹H NMR 3.59(2H, s), 7.04-7.10(3H, m), 7.27-7.33(2H, m), 7.94(2H, d, J = 8.4 Hz), 8.17(2H, d, J = 8.1 Hz), 8.21-8.25(1H, m), 8.51(1H, d, J = 2.6 Hz), 10.64(1H, s), 12.43(1H, brs). 761 —Cl —Cl —H 1 ¹H NMR 3.59(2H, s), 7.04-7.09(3H, m), 7.27-7.32(2H, m), 7.83(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.18-8.23(2H, m), 8.48(1H, d, J = 2.6 Hz), 10.55(1H, s), 12.37(1H, brs). 762 —Cl —Cl —H 2 ¹H NMR 2.51-2.58(2H, m), 2.81-2.86(2H, m), 7.01- 7.06(3H, m), 7.26(2H, d, J = 8.6 Hz), 7.84(1H, d, J = 8.4 Hz), 7.93-7.97(1H, m), 8.16-8.23(2H, m), 8.47(1H, d, J = 2.7 Hz), 10.54(1H, s), 12.13(1H, brs). 763 —H —CF₃ —H 2 ¹H NMR 2.56(2H, t, J = 7.5 Hz), 2.84(2H, t, J = 7.5 Hz), 7.03(2H, d, J = 8.6 Hz), 7.05(1H, d, J = 8.8 Hz), 7.27(2H, d, J = 8.6 Hz), 7.93(2H, d, J = 8.2 Hz), 8.17(2H, d, J = 8.2 Hz), 8.21(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.50(1H, d, J = 2.6 Hz), 10.63(1H, s), 12.16(1H, s).

TABLE 105

Reference Example No. R₃₃₃ R₃₃₄ M ¹H NMR (DMSO-d₆) δppm 764 —OCH₃ —H 0 3.76(3H, s), 7.09(1H, d, J = 8.9 Hz), 7.23(1H, d, J = 8.1 Hz), 7.59-7.63 (2H, m), 7.84(1H, d, J = 8.4 Hz), 7.93- 7.96(1H, m), 8.16-8.22(2H, m), 8.39(1H, d, J = 2.7 Hz), 10.53(1H, s), 13.00(1H, brs). 765 —H —OCH₃ 0 3.80(3H, s), 6.69(1H, dd, J = 8.4 Hz, 2.2 Hz), 6.90(1H, d, J = 2.2 Hz), 7.17(1H, d, J = 8.9 Hz), 7.73(1H, d, J = 8.4 Hz), 7.85(1H, d, J = 8.4 Hz), 7.97(1H, dd, J = 8.4 Hz, 2.2 Hz), 8.23-8.28(2H, m), 8.56(1H, d, J = 2.4 Hz), 10.62(1H, s), 12.56(1H, brs.) 766 —CH₃ —H 0 2.18(3H, s), 7.09-7.16(2H, m), 7.79-7.97(4H, m), 8.21- 8.26(2H, m), 8.47(1H, d, J = 2.2 Hz), 10.57(1H, s), 12.86(1H, brs). 767 —H —CH₃ 0 2.53(3H, s), 6.97-7.04(2H, m), 7.16(1H, d, J = 8.7 Hz), 7.77-7.98(3H, m), 8.23-8.27(2H, m), 8.54(1H, d, J = 2.6 Hz), 10.62(1H, s), 12.79(1H, brs). 768 —F —H 0 7.24(1H, d, J = 8.9 Hz), 7.39-7.45(1H, m), 7.70-8.05(4H, m), 8.23-8.28 (2H, m), 8.46(1H, d, J = 2.6 Hz), 10.64(1H, s), 13.55(1H, brs). 769 —Cl —H 0 7.25(1H, d, J = 8.9 Hz), 7.39(1H, d, J = 8.6 Hz), 7.84(1H, d, J = 8.4 Hz), 7.93-7.97(2H, m), 8.06(1H, d, J = 2.0 Hz), 8.22(1H, d, J = 2.0 Hz), 8.25-8.29(1H, m), 8.47(1H, d, J = 2.6 Hz), 10.61(1H, s), 13.31(1H, brs). 770 —OCH₃ —H 2 2.5-2.65(2H, m), 2.71-2.92(2H, m), 3.67(3H, s), 6.81(1H, dd, J = 8.1 Hz, 1.9 Hz), 6.95(1H, d, J = 8.9 Hz), 6.99- 7.05(2H, m), 7.82(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.10(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.20(1H, d, J = 2.0 Hz), 8.35(1H, m), 10.47(1H, s), 12.15(1H, brs). 771 —OC₂H₅ —H 2 1.06(3H, t, J = 7.0 Hz), 2.51-2.62(2H, m), 2.74-2.88(2H, m), 3.94(2H, q, J = 7.0 Hz), 6.80(1H, dd, J = 8.1 Hz, 1.8 Hz), 6.92-7.04(3H, m), 7.82(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.11(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.20(1H, d, J = 2.0 Hz), 8.36(1H, d, J = 2.7 Hz), 10.47(1H, s), 12.14(1H, brs) 772 —F —H 2 2.50-2.67(2H, m), 2.75-2.93(2H, m), 7.03-7.29(4H, m), 7.82(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.12-8.24(2H, m), 8.39(1H, d, J = 2.5 Hz), 10.53(1H, s), 12.18(1H, brs).

TABLE 106

Reference Example No. R₃₃₅ R₃₃₆ M ¹H NMR (DMSO-d₆) δppm 773 —OCH₃ —H 0 3.76(3H, s), 7.10(1H, d, J = 8.9 Hz), 7.23(1H, d, J = 8.1 Hz), 7.59-7.64 (2H, m), 7.93(2H, d, J = 8.1 Hz), 8.15- 8.23(3H, m), 8.42(1H, d, J = 2.2 Hz), 10.60(1H, s), 13.00(1H, brs). 774 —H —OCH₃ 0 3.80(3H, s), 6.69(1H, dd, J = 8.6 Hz, 2.2 Hz), 6.90(1H, d, J = 2.2 Hz), 7.17(1H, d, J = 8.6 Hz), 7.73(1H, d, J = 8.4 Hz), 7.95(2H, d, J = 8.4 Hz), 8.18(2H, d, J = 8.4 Hz), 8.29(1H, dd, J = 8.6 Hz, 2.7 Hz), 8.58(1H, d, J = 2.7 Hz), 10.69(1H, s), 12.51(1H, brs). 775 —CH₃ —H 0 1.99(3H, s), 7.09-7.17(2H, m), 7.79-7.83(1H, m), 7.91- 7.95(3H, m), 8.12-8.18(2H, m), 8.27(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.49(1H, d, J = 2.7 Hz), 10.64(1H, s), 12.87(1H, brs). 776 —H —CH₃ 0 2.54(3H, s), 6.98-7.05(2H, m), 7.17(1H, d, J = 8.7 Hz), 7.87-7.97(3H, m), 8.13-8.19(2H, m), 8.26-8.30(1H, m), 8.57(1H, d, J = 2.8 Hz), 10.70(1H, s), 12.81(1H, brs). 777 —F —H 0 7.26(1H, d, J = 8.9 Hz), 7.40-7.46(1H, m), 7.82-7.85(2H, m), 7.94(2H, d, J = 8.2 Hz), 8.17(2H, d, J = 8.2 Hz), 8.30(1H, dd, J = 8.9 Hz, 2.1 Hz), 8.49(1H, d, J = 2.1 Hz), 10.70(1H, s), 13.39(1H, brs). 778 —Cl —H 0 7.14(1H, d, J = 8.9 Hz), 7.19(1H, d, J = 8.2 Hz), 7.82- 7.86(1H, m), 7.92(2H, d, J = 8.4 Hz), 7.96(1H, d, J = 1.8 Hz), 8.20(2H, d, J = 8.2 Hz), 8.29(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.47(1H, d, J = 2.6 Hz), 10.86(1H, s). 779 —OCH₃ —H 2 2.57-2.63(2H, m), 2.83-2.89(2H, m), 3.69(3H, s), 6.84(1H, dd, J = 8.1 Hz, 1.8 Hz), 6.97(1H, d, J = 8.9 Hz), 7.01- 7.04(2H, m), 7.92(2H, d, J = 8.4 Hz), 8.14-8.18(3H, m), 8.40(1H, d, J = 2.5 Hz), 10.58(1H, s). 780 —OC₂H₅ —H 2 1.06(3H, t, mJ = 7.0 Hz), 2.47-2.67(2H, m), 2.72-2.91(2H, m), 3.94(2H, q, J = 7.0 Hz), 6.80(1H, dd, J = 8.0 Hz, 1.8 Hz), 6.94-7.05(3H, m), 7.91(2H, d, J = 8.3 Hz), 8.09- 8.19(3H, m), 8.38(1H, d, J = 2.6 Hz), 10.55(1H, s), 12.14(1H, brs). 781 —F —H 2 2.49-2.63(2H, m), 2.71-2.93(2H, m), 7.09(1H, dd, J = 8.3 Hz, 1.5 Hz), 7.14(1H, d, J = 8.9 Hz), 7.17-7.28(2H, m), 7.92(2H, d, J = 8.2 Hz), 8.15(2H, d, J = 8.2 Hz), 8.21(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.38-8.44(1H, m), 10.60(1H, s), 12.17(1H, brs).

TABLE 107

Reference Example No. R₃₃₇ R₃₃₈ R₃₃₉ ¹H NMR (DMSO-d₆) δppm 782 —Cl —Cl

7.20(1H, d, J = 8.7 Hz), 7.40(1H, dd, J = 8.7 Hz, 2.3 Hz), 7.60-7.67(1H, m), 7.82- 8.03(4H, m), 8.15(1H, d, J = 8.9 Hz), 8.26- 8.32(2H, m), 8.56-8.60(2H, m), 10.78(1H, s). 783 —CF₃ —H

7.18(1H, d, J = 8.7 Hz), 7.36(1H, dd, J = 8.7 Hz, 2.3 Hz), 7.63(1H, d, J = 2.0 Hz), 7.84-8.11(5H, m), 8.23(2H, d, J = 8.1 Hz), 8.34(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.54- 8.60(2H, m), 10.98(1H, s). 784 —Cl —Cl

7.19(1H, d, J = 8.7 Hz), 7.47(1H, dd, J = 9.4 Hz, 2.5 Hz), 7.57-7.63(1H, m), 7.73(1H, d, J = 2.5 Hz), 7.85(1H, d, J = 8.4 Hz), 7.96(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.10-8.14(2H, m), 8.23-8.28(2H, m), 8.52(1H, d, J = 2.5 Hz), 8.92(1H, d, J = 9.4 Hz), 10.60(1H, s), 13.20(1H, brs). 785 —CF₃ —H

7.20(1H, d, J = 8.7 Hz), 7.48(1H, dd, J = 9.4 Hz, 2.6 Hz), 7.57-7.63(1H, m), 7.73(1H, d, J = 2.5 Hz), 7.94(2H, d, J = 8.2 Hz), 8.11-8.19(4H, m), 8.29(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.55(1H, d, J = 2.5 Hz), 8.93(1H, d, J = 9.4 Hz), 10.68(1H, s), 13.21(1H, brs). 786 —Cl —Cl

7.24(1H, d, J = 8.1 Hz), 7.32(1H, d, J = 8.7 Hz), 7.58-7.64(1H, m), 7.69-7.77(1H, m), 7.85(1H, d, J = 8.4 Hz), 7.97(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.06-8.12 (1H, m), 8.20- 8.23(2H, m), 8.30(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.48(1H, d, J = 2.6 Hz), 9.02(1H, d, J = 8.7 Hz), 10.63(1H, s), 13.11(1H, brs). 787 —Cl —Cl

7.17(1H, d, ,J = 8.9 Hz), 7.38-7.43(1H, m), 7.53-7.59(2H, m), 7.76-7.86(2H, m), 7.93- 7.97(1H, m), 8.22-8.27(2H, m), 8.51(1H, d, J = 2.0 Hz), 10.60(1H, s), 13.15(1H, brs).

TABLE 108

Reference Example No. R₃₄₀ R₃₄₁ ¹H NMR (solvent) δppm 788 —H —Ac (DMSO-d₆) 1.85(3H, s), 4.26(2H, s), 7.13(1H, d, J = 8.8 Hz), 7.19(2H, d, J = 8.7 Hz), 7.42(2H, d, J = 8.7 Hz), 7.85(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 1.9 Hz, 8.4 Hz), 8.20-8.24(2H, m), 8.51(1H, d, J = 2.5 Hz), 12.77(1H, brs). 789 —H —CH₃ (DMSO-d₆) 2.98(3H, s), 4.01(2H, s), 6.65(1H, d, J = 9.1 Hz), 6.90-6.95(3H, m), 7.82(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 2.1 Hz, 8.4 Hz), 8.13(1H, dd, J = 2.7 Hz, 8.9 Hz), 8.22(1H, d, J = 2.1 Hz), 8.43(1H, d, J = 2.7 Hz), 10.54(1H, s). 790 —H —C₂H₅ (DMSO-d₆) 1.11(3H, t, J = 7.1 Hz), 3.39(2H, q, J = 7.1 Hz), 4.01(2H, s), 6.58(2H, d, J = 9.1 Hz), 6.90-6.95(3H, m), 7.81(1H, d, J = 8.4 Hz), 7.92(1H, dd, J = 2.0 Hz, 8.4 Hz), 8.11(1H, dd, J = 2.7 Hz, 8.9 Hz), 8.19(1H, d, J = 2.0 Hz), 8.41(1H, d, J = 2.7 Hz), 10.48(1H, s), 12.53(1H, brs). 791 —OCH₃ —CH₃ (DMSO-d₆) 3.01(3H, s), 3.67(3H, s), 4.12(2H, s), 6.20(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.39(1H, d, J = 2.8 Hz), 6.85-6.94(2H, m), 7.83(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.08(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.21(1H, d, J = 2.0 Hz), 8.36(1H, d, J = 2.5 Hz), 10.47(1H, s), 12.58(1H, brs). 792 —OCH₃ —C₂H₅ (DMSO-d₆) 1.15(3H, t, J = 7.1 Hz), 3.43(2H, q, J = 7.1 Hz), 3.65(3H, s), 4.06(2H, s), 6.13(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.30(1H, d, J = 2.6 Hz), 6.87-6.91(2H, m), 7.83(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.08(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.21(1H, d, J = 2.0 Hz), 8.36(1H, d, J = 2.6 Hz), 10.48(1H, s), 12.58(1H, brs). 793 —CH₃ —Ac (DMSO-d₆) 1.84(3H, s), 2.11(3H, s), 4.23(2H, s), 7.05-7.10(2H, m), 7.20-7.25 (1H, m), 7.32(1H, d, J = 2.2 Hz), 7.75-7.85(1H, m), 7.92(1H, dd, J = 2.2 Hz, 8.4 Hz), 8.10-8.20(2H, m), 8.43(1H, d, J = 2.6 Hz), 10.53(1H, s), 12.66(1H, brs). 794 —CH₃ —CH₃ (DMSO-d₆) 2.01(3H, s), 2.97(3H, s), 4.07(2H, s), 6.49(1H, dd, J = 8.8 Hz, 3.0 Hz), 6.57(1H, d, J = 3.0 Hz), 6.85(1H, d, J = 8.8 Hz), 6.90(1H, d, J = 8.9 Hz), 7.82(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.11(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.20(1H, d, J = 2.0 Hz), 8.39(1H, d, J = 2.7 Hz), 10.47(1H, s), 12.51(1H, brs). 795 —F —Ac (CDCl₃ + DMSO-d₆) 1.99(3H, s), 4.35(2H, s), 7.03(1H, d, J = 8.9 Hz), 7.21-7.31 (3H, m), 7.57(1H, d, J = 8.4 Hz), 7.90(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.19(1H, d, J = 2.0 Hz), 8.32(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.46(1H, d, J = 2.5 Hz), 10.12(1H, s). 796 —F —CH₃ (CDCl₃ + DMSO-d₆) 3.04(3H, s), 3.98(2H, s), 6.40-6.49(2H, m), 6.90(1H, d, J = 8.9 Hz), 7.02(1H, t, J = 8.7 Hz), 7.52(1H, d, J = 8.4 Hz), 7.85(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.14(1H, d, J = 2.0 Hz), 8.23(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.34(1H, d, J = 2.5 Hz), 9.77(1H, s). 797 —F —C₂H₅ (CDCl₃) 1.26(3H, t, J = 7.1 Hz, 3.44(2H, q, J = 7.1 Hz), 4.03(2H, s), 6.39-6.52 (2H, m), 6.96(1H, d, J = 9.7 Hz), 7.06(1H, t, J = 8.9 Hz), 7.55(1H, d, J = 8.4 Hz), 7.69(1H, dd, J = 8.6 Hz, 2.1 Hz), 7.96-7.97(2H, m), 8.15-8.18(2H, m).

TABLE 109

Reference Example No. R₃₄₂ R₃₄₃ ¹H NMR (solvent) δppm 798 —H —Ac (DMSO-d₆) 1.85(3H, s), 4.26(2H, s), 7.13(1H, d, J = 8.8 Hz), 7.18(2H, d, J = 8.7 Hz), 7.42(2H, d, J = 8.7 Hz), 7.94(2H, d, J = 8.2 Hz), 8.16(2H, d, J = 8.2 Hz), 8.25(1H, dd, J = 2.5 Hz, 8.8 Hz), 8.54(1H, d, J = 2.5 Hz), 10.66(1H, s), 12.70(1H, brs). 799 —H —CH₃ (DMSO-d₆) 2.99(3H, s), 4.09(2H, s), 6.67(2H, d, J = 9.0 Hz), 6.96(3H, d, J = 9.0 Hz), 7.93(2H, d, J = 8.2 Hz), 8.16(2H, d, J = 8.2 Hz), 8.12-8.20(1H, m), 8.46(1H, d, J = 2.3 Hz), 10.59(1H, s), 12.58(1H, brs). 800 —H —C₂H₅ (DMSO-d₆) 1.13(3H, t, J = 7.1 Hz), 3.38(2H, q, J = 7.1 Hz), 4.00(2H, s), 6.65(1H, d, J = 8.9 Hz), 6.73(1H, d, J = 8.9 Hz), 6.92-6.97(3H, m), 7.93(2H, d, J = 8.1 Hz), 8.15-8.18(3H, m), 8.46(1H, s), 10.59(1H, s). 801 —OCH₃ —CH₃ (DMSO-d₆) 3.01(3H, s), 3.67(3H, s), 4.12(2H, s), 6.20(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.39(1H, d, J = 2.5 Hz), 6.83- 6.95(2H, m), 7.93(2H, d, J = 8.3 Hz), 8.09-8.17(3H, m), 8.38(1H, d, J = 2.6 Hz), 10.56(1H, s), 12.58(1H, brs). 802 —OCH₃ —C₂H₅ (DMSO-d₆) 1.15(3H, t, J = 7.1 Hz), 3.43(2H, q, J = 7.1 Hz), 3.66(3H, s), 4.06(2H, s), 6.14(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.31(1H, d, J = 2.8 Hz), 6.88-6.92(2H, m), 7.93(2H, d, J = 8.4 Hz), 8.09-8.17(3H, m), 8.39(1H, d, J = 2.5 Hz), 10.55(1H, s), 12.58(1H, brs). 803 —CH₃ —Ac (DMSO-d₆) 1.84(3H, s), 2.11(3H, s), 4.23(2H, s), 7.05- 7.10(2H, m), 7.23 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.33(1H, d, J = 2.4 Hz), 7.86(1H, d, J = 8.3 Hz), 7.91(2H, d, J = 8.3 Hz), 8.14(2H, d, J = 8.3 Hz), 8.20(1H, dd, J = 2.7 Hz, 8.9 Hz), 8.45(1H, d, J = 2.7 Hz), 10.61(1H, s), 12.67 (1H, brs). 804 —CH₃ —CH₃ (DMSO-d₆) 2.01(3H, s), 2.97(3H, s), 4.06(2H, s), 6.49(1H, dd, J = 8.8 Hz, 3.1 Hz), 6.57(1H, d, J = 2.9 Hz), 6.85(1H, d, J = 8.8 Hz), 6.91(1H, d, J = 8.9 Hz), 7.91(2H, d, J = 8.3 Hz), 8.04-8.23(3H, m), 8.41(1H, d, J = 2.6 Hz), 10.56(1H, s), 12.11-12.98(1H, m). 805 —F —Ac (CDCl₃) 1.96(3H, s), 4.32(2H, s), 7.09-7.31(4H, m), 7.75(2H, d, J = 8.4 Hz), 8.02(2H, d, J = 8.3 Hz), 8.20(1H, d, J = 2.6 Hz), 8.40(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.44(1H, s). 806 —F —CH₃ (CDCl₃ + DMSO-d₆) 3.08(3H, s), 4.02(2H, s), 6.47-6.52(2H, m), 6.92(1H, d, J = 8.7 Hz), 7.06(1H, t, J = 9.0 Hz), 7.73(2H, d, J = 8.4 Hz), 8.11(2H, d, J = 8.4 Hz), 8.26(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.39(1H, d, J = 2.5 Hz), 9.76(1H, s). 807 —F —C₂H₅ (CDCl₃ + DMSO-d₆) 1.23(3H, t, J = 7.1 Hz), 3.45(2H, q, J = 7.1 Hz), 3.97 (2H, s), 6.39-6.48(2H, m), 6.91(1H, d, J = 8.7 Hz), 7.04(1H, t, J = 9.1 Hz), 7.73(2H, d, J = 7.9 Hz), 8.12(2H, d, J = 7.9 Hz), 8.25(1H, d, J = 9.1 Hz), 8.42(1H, d, J = 2.5 Hz), 9.92(1H, s). 808 —F —(CH₂)₂CH₃ (CDCl₃ + DMSO-d₆) 0.96(3H, t, J = 7.2 Hz), 1.61-1.72(2H, m), 3.33(2H, t, J = 7.6 Hz), 3.99(2H, s), 6.37-6.48(2H, m), 6.93(1H, d, J = 8.8 Hz), 7.04 (1H, t, J = 9.1 Hz), 7.73(2H, d, J = 8.1 Hz), 8.09(2H, d, J = 8.1 Hz), 8.26 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.36(1H, d, J = 2.5 Hz), 9.45(1H, s).

TABLE 110

Reference Example No. R₃₄₄ R₃₄₅ R₃₄₆ ¹H NMR (solvent) δppm 809 —Cl —Cl —N(Ac)(CH₂)₂COOH (DMSO-d₆) 1.71(3H, s), 2.39(2H, t, J = 7.5 Hz), 3.78(2H, t, J = 7.5 Hz), 7.08(1H, d, J = 8.8 Hz), 7.14(2H, d, J = 8.6 Hz), 7.31(2H, d, J = 8.6 Hz), 7.80(1H, d, J = 8.4 Hz), 7.91 (1H, dd, J = 2.1 Hz, 8.4 Hz), 8.15-8.21(2H, m), 8.49(1H, d, J = 2.5 Hz), 10.55(1H, s), 12.20(1H, brs). 810 —CF₃ —H —N(Ac)(CH₂)₂COOH (DMSO-d₆) 1.71(3H, s), 2.40(2H, t, J = 7.3 Hz), 3.78(2H, t, J = 7.3 Hz), 7.09(1H, d, J = 8.7 Hz), 7.14(2H, d, J = 8.1 Hz), 7.31(2H, d, J = 8.1 Hz), 7.90(2H, d, J = 8.1 Hz), 8.12 (2H, d, J = 8.1 Hz), 8.21(1H, d, J = 8.7 Hz), 8.52(1H, s), 10.63(1H, s), 12.25(1H, brs). 811 —Cl —Cl —CH(CH₃)CH₂COOH (CDCl₃ − CD₃OD) 1.26(3H, d, J = 7.0 Hz), 2.42-2.61(2H, m), 3.17-3.28(1H, m), 6.84(1H, d, J = 8.9 Hz), 6.98(2H, d, J = 8.5 Hz), 7.20(2H, d, J = 8.5 Hz), 7.50(1H, d, J = 8.4 Hz), 7.73(1H, dd, J = 8.5 Hz, 2.1 Hz), 8.01(1H, d, J = 2.1 Hz), 8.14(1H, d, J = 2.7 Hz), 8.26(1H, dd, J = 8.9 Hz, 2.7 Hz). 812 —CF₃ —H —CH(CH₃)CH₂COOH (CDCl₃ − CD₃OD) 1.28(3H, d, J = 7.0 Hz), 2.44-2.61(2H, m), 3.18-3.29(1H, m), 6.88(1H, d, J = 8.9 Hz), 7.00(2H, d, J = 8.5 Hz), 7.20(2H, d, J = 8.5 Hz), 7.70(2H, d, J = 8.2 Hz), 7.99(2H, d, J = 8.2 Hz), 8.17(1H, d, J = 2.6 Hz), 8.28(1H, dd, J = 8.9 Hz, 2.6 Hz). 813 —CF₃ —H —CH═CHCOOH (DMSO-d₆) 6.49(1H, d, J = 16.0 Hz), (trans) 7.15(3H, d, J = 8.8 Hz), 7.61(1H, d, J = 16.0 Hz), 7.74(2H, d, J = 8.8 Hz), 7.94(2H, d, J = 8.3 Hz), 8.17(2H, d, J = 8.3 Hz), 8.26(1H, dd, J = 8.8 Hz, 2.7 Hz), 8.55(1H, d, J = 2.7 Hz), 10.67(1H, s), 12.36(1H, s). 814 —CF₃ —H

(CDCl₃) 1.34(6H, s), 2.79(3H, s), 6.98(1H, d, J = 8.9 Hz), 7.10(2H, d, J = 8.9 Hz), 7.21(2H, d, J = 9.1 Hz), 7.76(2H, d, J = 8.2 Hz), 8.01(2H, d, J = 8.1 Hz), 8.10(1H, brs), 8.24(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.31(1H, d, J = 2.3 Hz).

TABLE 111

Reference Example No. R₃₄₇ R₃₄₈ R₃₄₉ R₃₅₀ M ¹H NMR (solvent) δppm 815 —Cl —Cl —H —F 0 (DMSO-d₆) 4.29(2H, d, J = 5.6 Hz), 6.46(1H, t, J = 5.9 Hz), 6.94(1H, d, J = 8.7 Hz), 7.15(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.20 (1H, d, J = 8.3 Hz), 7.36(1H, dd, J = 8.3 Hz, 1.8 Hz), 7.47(1H, d, J = 2.8 Hz), 7.59(1H, d, J = 8.3 Hz), 7.63(1H, d, J = 2.0 Hz), 7.72-7.77(2H, m). 816 —CF₃ —H —H —F 0 (DMSO-d₆) 4.37(2H, d, J = 5.3 Hz), 6.47(1H, brs), 6.89(1H, d, J = 8.7 Hz), 7.06-7.12(1H, m), 7.13(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.45((1H, d, J = 3.0 Hz), 7.58(2H, d, J = 8.1 Hz), 7.65-7.69(2H, m), 7.70(2H, d, J = 8.1 Hz). 817 —CF₃ —H —CH₃ —H 0 (DMSO-d₆) 3.03(3H, s), 4.66(2H, s), 6.82(2H, d, J = 8.7 Hz), 6.87(1H, d, J = 8.9 Hz), 7.29(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.45 (21H, d, J = 8.1 Hz), 7.68-7.72(3H, m), 7.82(2H, d, J = 8.7 Hz). 818 —CF₃ —H —C₂H₅ —H 0 (DMSO-d₆) 1.13(3H, t, J = 7.1 Hz), 3.49(2H, q, J = 7.1 Hz), 4.61(2H, s), 6.81(2H, d, J = 8.6 Hz), 6.84(1H, d, J = 8.9 Hz), 7.22(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.47(2H, d, J = 8.1 Hz), 7.62(1H, d, J = 3.3 Hz), 7.70(2H, d, J = 8.3 Hz), 7.80(2H, d, J = 8.7 Hz). 819 —Cl —Cl —CH₃ —OCH₃ 2 (CDCl₃) 2.66(2H, t, J = 7.7 Hz), 2.93(2H, t, J = 7.7 Hz), 2.95 (3H, s), 3.75(3H, s), 4.35(2H, s), 6.68-6.88(3H, m), 6.90-7.00 (1H, m), 7.00- 7.17(2H, m), 7.31(1H, d, J = 2.0 Hz), 7.37(1H, d, J = 8.2 Hz), 7.65(1H, d, J = 3.0 Hz), 8.21(1H, brs). 820 —CF₃ —H —CH₃ —OCH₃ 2 (DMSO-d₆) 2.41-2.62(2H, m), 2.69-2.85(2H, m), 2.96(3H, s), 3.64(3H, s), 4.58(2H, s), 6.70- 6.79(2H, m), 6.88(1H, d, J = 8.0 Hz), 6.95(1H, d, J = 1.8 Hz), 7.25(1H, dd, J = 9.2 Hz, 3.2 Hz), 7.42(2H, d, J = 8.0 Hz), 7.52(1H, d, J = 3.2 Hz), 7.67(2H, d, J = 8.0 Hz), 11.64-12.51(1H, m). 821 —Cl —Cl —CH₃ —OC₂H₅ 2 (DMSO-d₆) 1.03(3H, t, J = 7.0 Hz), 2.523(2H, t, J = 7.6 Hz), 2.78(2H, t, J = 7.6 Hz), 3.89(2H, q, J = 7.0 Hz), 4.49(2H, s), 6.70-6.80(2H, m), 6.88(1H, d, J = 8.0 Hz), 6.92(1H, d, J = 1.9 Hz), 7.19(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.26(1H, dd, J = 9.0 Hz, 3.2 Hz), 7.45(1H, d, J = 2.0 Hz), 7.52(1H, d, J = 3.2 Hz), 7.56(1H, d, J = 8.3 Hz), 11.81-12.30(1H, m). 822 —Cl —Cl —CH₃ —F 2 (DMSO-d₆) 2.55(2J, t, J = 7.6 Hz), 2.80(2H, t, J = 7.6 Hz), 2.96(3H, s), 4.50(2H, s),6.92(1H, d, J = 8.9 Hz), 7.00-7.22 (4H, m), 7.22-7.38(1H, m), 7.38-7.40(1H, m), 7.40-7.55(2H, m), 12.10(1H, brs). 823 —Cl —Cl —C₂H₅ —F 2 (CDCl₃) 1.17(3H, t, J = 7.0 Hz), 2.66(2H, t, J = 7.7 Hz), 2.93 (2H, t, J = 7.7 Hz), 3.40(2H, q, J = 7.0 Hz), 4.36(2H, s), 6.72-6.86(1H, m), 6.90- 7.15(5H, m), 727-7.35(1H, m), 7.36 (1H, d, J = 8.2 Hz), 7.59(1H, d, J = 3.2 Hz).

TABLE 112

Reference Example No. R₃₅₁ R₃₅₂ R₃₅₃ R₃₅₄ ¹H NMR (solvent) δppm 824 —CF₃ —H —CH₃ —H (DMSO-d₆) 2.50-2.54(2H, m), 2.79(2H, t, J = 7.6 Hz), 3.02(3H, s), 4.64(2H, s), 6.86(1H, d, J = 8.9 Hz), 6.89(2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.7 Hz), 7.29(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.44(2H, d, J = 7.9 Hz), 7.69(2H, d, J = 7.9 Hz), 7.64(1H, d, J = 3.1 Hz). 825 —CF₃ —H —CH₃ —OC₂H₅ (DMSO-d₆) 1.03(3H, t, J = 7.0 Hz), 2.47-2.59(2H, m), 2.71-2.83 (2H, m), 2.97(3H, s), 3.89(2H, q, J = 7.0 Hz), 4.59(2H, s), 6.69-6.79 (2H, m), 6.88(1H, d, J = 8.0 Hz), 6.91(1H, d, J = 1.9 Hz), 7.26(1H, dd, J = 9.0 Hz, 3.1 Hz), 7.41(2H, d, J = 8.0 Hz), 7.52(1H, d, J = 3.1 Hz), 7.66(2H, d, J = 8.0 Hz), 11.85-12.31(1H, m). 826 —CF₃ —H —CH₃ —F (CDCl₃) 2.67(2H, t, J = 7.7 Hz), 2.94(2H, t, J = 7.7 Hz), 3.00(3H, s), 4.49(2H, s), 6.86(1H, d, J = 8.9 Hz), 6.90-7.16(4H, m), 7.33(2H, d, J = 8.1 Hz), 7.57(2H, d, J = 8.1 Hz), 7.64(1H, d, J = 3.1 Hz). 827 —CF₃ —H —C₂H₅ —H (DMSO-d₆) 1.11(3H, t, J = 7.0 Hz), 2.42-2.57(2H, m), 2.71-2.82 (2H, m), 3.47(2H, q, J = 7.0 Hz), 4.58(2H, s), 6.82(1H, d, J = 8.9 Hz), 6.84-6.91(2H, m), 7.13- 7.21(2H, m), 7.20(1H, dd, J = 8.9 Hz, 3.1 Hz), 7.45(2H, d, J = 8.1 Hz), 7.57(1H, d, J = 3.1 Hz), 7.68(2H, d, J = 8.1 Hz), 12.06(1H, brs). 828 —Cl —Cl C₂H₅ OCH₃ (CDCl₃) 1.16(3H, t, J = 7.1 Hz), 2.55-2.78(2H, m), 2.94(2H, t, J = 7.7 Hz), 3.39(2H, q, J = 7.1 Hz), 3.77(3H, s), 4.35(2H, s), 6.70-6.88(3H, m), 6.92- 7.13(3H, m), 7.32(1H, d, J = 2.0 Hz), 7.36(1H, d, J = 8.2 Hz), 7.59(1H, d, J = 3.1 Hz). 829 —CF₃ —H —C₂H₅ —OCH₃ (DMSO-d₆) 1.09(3H, t, J = 7.0 Hz), 2.48-2.61(2H, m), 2.72-2.86 92H, m), 3.40(2H, q, J = 7.0 Hz), 3.64(3H, s), 4.54(2H, s), 6.73(1H, d, J = 9.0 Hz), 6.74(1H, dd, J = 8.0 Hz), 1.9 Hz), 6.87(1H, d, J = 8.0 Hz), 6.95(1H, d, J = 1.9 Hz), 7.18(2H, dd, J = 9.0 Hz, 3.2 Hz), 7.39- 7.49(3H, m), 7.62-7.71(2H, m), 11.90-12.31(1H, m). 830 —Cl —Cl —C₂H₅ —OC₂H₅ (DMSO-d₆) 0.95-1.11(6H, m), 2.41-2.57(2H, m), 2.77(2H, t, J = 7.7 Hz), 3.29-3.47(2H, m), 3.88(2H, q, J = 7.0 Hz), 4.44(2H, s),6.73(1H, dd, J = 8.0 Hz, 1.9 Hz), 6.74(1H, d, J = 9.0 Hz), 6.88(1H, d, J = 8.0 Hz), 6.91(1H, d, J = 1.9 Hz), 7.15-7.24(2H, m), 7.41-7.48 (2H, m), 7.55(1H, d, J = 8/.2 Hz), 11.60-12.50(1H, m). 831 —CF₃ —H —C₂H₅ —OC₂H₅ (DMSO-d₆) 1.02(3H, t, J = 7.0 Hz), 1.08(3H, t, J = 7.0 Hz), 2.46-2.59(2H, m), 2.71-2.83(2H, m), 3.43(2H, q, J = 7.0 Hz), 3.89 (2H, q, J = 7.0 Hz), 6.69-6.78(2H, m), 6.87(1H, d, J = 8.0 Hz), 6.91 (1H, d, J = 1.8 Hz), 7.19(1H, dd, J = 9.0 Hz, 3.2 Hz), 7.39- 7.49(3H, m), 7.61-7.69(2H, m), 11.92-12.22(1H, m). 832 —CF₃ —H —C₂H₅ —F (CDCl₃) 1.19(3H, t, J = 7.1 Hz), 2.67(2H, t, J = 7.7 Hz), 2.93(2H, t, J = 7.7 Hz), 3.43(2H, q, J = 7.1 Hz),, q, J H 4.48(2H, s), 6.83(1H, d, J = 9.0 Hz), 6.90-7.20(4H, m), 7.34(2H, d, J = 8.2 Hz), 7.50-7.65(3H, m)

TABLE 113

Reference Example No. R₃₅₅ R₃₅₆ R₃₅₇ R₃₅₈ R₃₅₉ Form ¹H NMR (solvent) δppm 833 —CF₃ —H —CH₃ —H —COOH free (DMSO-d₆) 1.45(3H, t, J = 6.8 Hz), 4.61(1H, dt, J = 6.8 Hz, 6.8 Hz), 6.53 (1H, d, J = 6.8 Hz), 6.85(1H, d, J = 8.6 Hz), 6.97(2H, d, J = 8.7 Hz), 7.04(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.51(1H, d, J = 3.0 Hz), 7.62(2H, d, J = 8.3 Hz), 7.70 (2H, d, J = 8.3 Hz), 7.89(2H, d, J = 8.9 Hz), 12.79(1H, brs). 834 —CF₃ —H —CH₃ —CH₃ —COOH free (DMSO-d₆) 1.54(3H, d, J = 6.8 Hz), 2.73(3H, s), 5.23(1H, q, J = 6.8 Hz), 7.00(1H, d, J = 8.9 Hz), 7.05(2H, d, J = 8.7 Hz), 7.46(1H, dd, J = 9.1 Hz, 3.3 Hz), 7.54(2H, d, J = 8.1 Hz), 7.72(2H, d, J = 8.4 Hz), 7.84(1H, d, J = 3.3 Hz), 7.93(2H, d, J = 8.6 Hz) 835 —CF₃ —H —H —CH₃

dihydro- chloride (DMSO-d₆) 1.81(3H, s), 3.05(3H, s), 4.22(2H, s), 4.67(2H, s), 6.95(1H, d, J = 8.7 Hz), 7.04(2H, d, J = 8.6 Hz), 7.28-7.40 (1H, m), 7.35(2H, d, J = 8.6 Hz), 7.45(2H, d, J = 8.1 Hz), 7.62-7.80 (1H, m), 7.70(2H, d, J = 8.1 Hz). 836 —Cl —Cl —H —CH₃

dihydro- chloride (CDCl₃) 1.81(3H, s), 3.02(3H, s), 4.23 (2H, s), 4.57(2H, s), 6.95(1H, d, J = 8.8 Hz), 7.04(2H, d, J = 8.7 Hz), 7.22(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.32-7.40(1H, m), 7.35(2H, d, J = 8.7 Hz), 7.51(1H, d, J = 2.0 Hz), 7.59(1H, d, J = 8.2 Hz), 7.71(1H, d, J = 3.0 Hz). 837 —CF₃ —H —H —(CH₂)₂OCH₃ —(CH₂)₂COOH free (DMSO-d₆) 2.43-2.57(2H, m), 2.71-2.82(2H, m), 3.25(3H, s), 3.48-3.58(2H, m), 3.59-3.68(2H, m), 4.66 (2H, s), 6.80(1H, d, J = 8.9 Hz), 6.83-6.90(2H, m), 7.11-7.25(3H, m), 7.44(2H, d, J = 8.0 Hz), 7.56(1H, d, J = 3.1 Hz), 7.67(2H, d, J = 8.0 Hz), 12.09 (1H, brs).

TABLE 114

Reference Example No. R₃₆₀ R₃₆₁ R₃₆₂ Xa₂₆ Xa₂₇ ¹H NMR (solvent) δppm or MS 838 —Cl —Cl —OCH₃ —CH═CH— —CH₂— ¹H NMR (DMSO-d₆) 2.57- (trans) 2.63(2H, m), 2.83-2.88(2H, m), 3.68(3H, s), 6.84(1H, dd, J = 8.1 Hz, 1.7 Hz), 6.98-7.05(3H, m), 7.20 (1H, d, J = 16.5 Hz), 7.36(1H, d, J = 16.5 Hz), 7.54- 7.65(2H, m), 7.87(1H, d, J = 1.8 Hz), 8.07-8.11(1H, m), 8.22(1H, d, J = 2.1 Hz), 12.20(1H, brs). 839 —CF₃ —H —OCH₃ —CH═CH— —CH₂— ¹H NMR (DMSO-d₆) 2.58- (trans) 2.63(2H, m), 2.83-2.89(2H, m), 3.68(3H, s), 6.82-6.86 (1H, m), 6.99-7.06(3H, m), 7.31(1H, d, J = 16.5 Hz), 7.41(1H, d, J = 16.5 Hz), 7.71-7.81(4H, m), 8.15(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.27(1H, d, J = 2.1 Hz), 12.18(1H, brs). 840 —CF₃ —H —OCH₃ —CO— —CH₂— ¹H NMR (DMSO-d₆) 2.57- 2.63(2H, m), 2.83-2.89(2H, m), 3.70(3H, s), 6.86(1H, dd, J = 8.1 Hz, 2.0 Hz), 7.06-7.15(3H, m), 7.90-7.97(4H, m), 8.18- 8.22(1H, m), 8.50 (1H, dd, J = 2.5 Hz, 0.7 Hz), 12.19(1H, brs). 841 —CF₃ —H —CH₃ —CO— —N(C₂H₅)— ¹H NMR (CDCl₃) 1.23(3H, t, J = 7.1 Hz), 2.12(3H, s), 3.467(2H, q, J = 7.1 Hz), 4.04(2H, s), 5.77 (1H, brs), 6.55-6.59(2H, m), 6.97(2H, d, J = 8.7 Hz), 7.73- 7.89(4H, m), 8.17-8.21(1H, m), 8.58(1H, d, J = 2.3 Hz). 842 —Cl —Cl —H —NHCONH— none MS 431(M⁺)

TABLE 115

Reference Example No. R₃₆₃ R₃₆₄ Form ¹H NMR (solvent) δppm 843 —H

hydro- chloride (DMSO-d₆) 2.94(3H, s), 3.10-3.59(7H, m), 4.02- 4.39(5H, m), 6.07(2H, s), 6.68(2H, d, J = 9.1 Hz), 6.74-7.06(5H, m), 7.25(1H, brs), 8.23(1H, dd, J = 8.7 Hz, 2.3 Hz), 8.65(1H, d, J = 2.3 Hz), 11.23(1H, brs). 844 —H —NO₂ free (CDCl₃) 7.13(1H, d, J = 8.5 Hz), 7.35(2H, d, J = 9.1 Hz), 8.33(2H, d, J = 9.1 Hz), 8.41(1H, dd, J = 8.5 Hz, 2.5 Hz), 8.89(1H, d, J = 2.5 Hz). 845 —H

free (DMSO-d₆) 2.47(H, brs), 3.31-3.53(6H, m), 7.16(1H, d, J = 8.6 Hz), 7.23-7.34(7H, m), 7.45-7.48(2H, m), 8.31(1H, dd, J = 8.6 Hz, 2.4 Hz), 8.68(1H, d, J = 2.4 Hz), 13.20(1H, brs). 846 —H

free (DMSO-d₆) 3.36-3.55(8H, m), 3.58(2H, s), 6.00 (2H, s), 6.78-6.92(3H, m), 7.17(1H, d, J = 8.6 Hz), 7.26(2H, d, J = 8.6 Hz), 7.48(2H, d, J = 8.4 Hz), 8.31(1H, dd, J = 2.3 Hz, 8.6 Hz), 8.68(1H, d, J = 2.2 Hz). 847 —H

free (DMSO-d₆) 2.50(4H, brs), 2.63-2.68(2H, m), 2.81- 2.86(2H, m), 3.48-3.61(6H, m), 6.01(2H, s), 6.81- 6.90(2H, m), 6.96(1H, s), 7.06-7.10(3H, m), 7.30(2H, d, J = 8.6 Hz), 8.25-8.38(1H, m), 8.66(1H, d, J = 2.7 Hz), 12.58(1H, brs). 848 —CH₃ —NO₂ free (DMSO-d₆) 2.22(3H, s), 7.28(1H, dd, J = 8.6 Hz, 0.7 Hz), 7.40(1H, d, J = 8.9 Hz), 8.14(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.28(1H, d, J = 2.6 Hz), 8.36(1H, dd, J = 8.6 Hz, 2.3 Hz), 8.65(1H, dd, J = 2.3 Hz, 0.7 Hz).

TABLE 116

Reference Example No. R₃₆₅ R₃₆₆ R₃₆₇ ¹H NMR (solvent) δppm 849 —NO₂ —CH₃ —H (DMSO-d₆) 2.06(3H, s), 7.14(1H, d, J = 8.6 Hz), 7.26(1H, d, J = 9.1 Hz), 7.64(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.74(1H, d, J = 2.5 Hz), 8.62(1H, dd, J = 9.1 Hz, 3.0 Hz), 9.02(1H, d, J = 2.8 Hz), 10.75(1H, brs). 850 —NO₂ —CH₃ —CH₃ (DMSO-d₆) 2.09(3H, s), 3.26(3H, s), 7.20- 7.36(4H, m), 8.64(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03(1H, d, J = 2.6 Hz). 851 4-CF₃PhNHCO— —CH₃ —H (DMSO-d₆) 2.08(3H, s), 7.11(1H, d, J = 8.7 Hz), 7.16(1H, d, J = 8.7 Hz), 7.64(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.72-7.75(3H, m), 7.98(2H, d, J = 8.6 Hz), 8.37(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.69(1H, d, J = 2.5 Hz), 10.62(1H, brs), 10.74(1H, brs). 852 4-CF₃PhOCH₂— —H —H (DMSO-d₆) 5.17(2H, s), 7.06(1H, d, J = 8.4 Hz), 7.13(2H, d, J = 8.9 Hz), 7.21(2H, d, J = 8.6 Hz), 7.67(2H, d, J = 8.4 Hz), 7.79(2H, d, J = 9.1 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.5 Hz), 8.25(1H, d, J = 2.0 Hz), 10.78(1H, brs). 853 4-CF₃PhOCH₂— —CH₃ —H (CDCl₃) 2.18(3H, s), 5.05(2H, s), 7.01- 7.08(5H, m), 7.51-7.58(4H, m), 7.83- 7.87(1H, m), 8.20(1H, d, J = 2.1 Hz), 9.02(1H, brs). 854 4-CF₃PhOCH₂— —CH₃ —CH₃ (DMSO-d₆) 2.09(3H, s), 3.25(3H, s), 5.17(2H, s), 7.10(1H, d, J = 8.4 Hz), 7.11(1H, d, J = 8.4 Hz), 7.17-7.23(3H, m), 7.32(1H, d, J = 2.3 Hz), 7.67(2H, d, J = 8.7 Hz), 7.98(1H, dd, J = 8.4 Hz, 2.3 Hz), 8.24(1H, d, J = 2.3 Hz).

TABLE 117

Reference Example No. R₃₆₈ R₃₆₉ R₃₇₀ ¹H NMR (solvent) δppm 855 3,4-Cl₂PhSO₂NH— —F —CH₃ (DMSO-d₆) 2.96(3H, s), 4.11(2H, s), 6.43(1H, dd, J = 8.9 Hz, 2.1 Hz), 6.58(1H, dd, J = 14.4 Hz, 3.0 Hz), 6.97- 7.02(2H, m), 7.53(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.63(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.77(1H, d, J = 2.5 Hz), 7.86(1H, d, J = 8.6 Hz), 7.88(1H, d, J = 2.1 Hz), 10.40(1H, s), 12.61(1H, brs). 856 3,4-Cl₂PhNHCO— —OCH₃ —C₂H₅ (CDCl₃) 1.26(3H, t, J = 7.1 Hz), 3.45(2H, q, J = 7.1 Hz), 3.69(3H, s), 4.08(2H, s), 6.24(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.31(1H, d, J = 2.6 Hz), 6.95(1H, d, J = 8.7 Hz), 7.00(1H, d, J = 8.7 Hz), 7.29- 7.50(1H, m), 7.55(1H, dd, J = 8.9 Hz, 2.5 Hz), 7.88(1H, d, J = 2.5 Hz), 8.24(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.56(1H, brs), 8.73(1H, d, J = 2.0 Hz).

Reference Example 857 Production of 3-{4-[5-(3,4-dichlorobenzylmethylamino)pyridin-2-yloxy]phenyl}propionic acid

To a solution of ethyl 3-{4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}propionate (1.63 g, 3.7 mmol) in ethanol (30 mL) were added 37% aqueous formaldehyde (2.0 mL, 22 mmol) and acetic acid (0.21 mL, 3.7 mmol), and the resulting solution was stirred at room temperature for 1 hour. To this solution was then added sodium cyanoborohydride (0.46 g, 7.3 mmol) at 0° C., and the resulting solution was stirred at the same temperature for 1 hour. To this solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.55 g of ethyl 3-{4-[5-(3,4-dichlorobenzylmethylamino)pyridin-2-yloxy]phenyl}propionate. This product was dissolved in ethanol (40 mL), and to the resulting solution was added 10% aqueous sodium hydroxide (2.7 mL, 6.7 mmol) and stirred at room temperature for 2 hours. The resulting solution was then acidified by adding 10% hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 1.44 g of the title compound.

Appearance: Colorless oil

¹H NMR (DMSO-d₆) δ 2.38-2.60 (2H, m), 2.78 (2H, t, J=7.6 Hz), 4.52 (2H, s), 6.81-6.92 (3H, m), 7.12-7.23 (3H, m), 7.28 (1H, dd, J=8.9 Hz, 3.3 Hz), 7.48 (1H, d, J=1.9 Hz), 7.57 (1H, d, J=8.2 Hz), 7.63 (1H, d, J=3.3 Hz), 11.70-12.40 (1H, m).

The following compound was produced in the same manner as in Reference Example 857.

Reference Example 858 3-(4-{5-[(3,4-Dichlorobenzyl)ethylamino]pyridin-2-yloxy}phenyl) propionic acid

¹H NMR (DMSO-d₆) δ 1.09 (3H, t, J=6.9 Hz), 2.37-2.59 (2H, m), 2.64-2.83 (2H, m), 3.45 (2H, q, J=6.9 Hz), 4.48 (2H, s), 6.82 (1H, d, J=8.9 Hz), 6.85-6.92 (2H, m), 7.12-7.25 (4H, m), 7.48 (1H, d, J=1.8 Hz), 7.54-7.61 (2H, m), 11.77-12.38 (1H, m).

Reference Example 859 Production of N-[2-(4-formylphenoxy)-5-pyridyl]-3,4-dichlorobenzamide

To a solution of 4-[(5-amino-2-pyridyl)oxy]benzaldehyde ethylene acetal (5.27 g, 20.4 mmol) and triethylamine (3.41 mL, 24.5 mmol) in THF (80 mL) was added dropwise a solution of 3,4-dichlorobenzoyl chloride (4.49 g, 21.4 mmol) in THF (30 mL) under ice cooling. The resulting solution was stirred for 2 hours at the same temperature. The reaction solution was concentrated under reduced pressure, to the residue, 80% acetic acid (55 mL) was added, and the mixture was heated at 80° C. with stirring for 1 hour. The reaction solution was concentrated under reduced pressure and to the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The obtained solid was recrystallized from isopropanol, to thereby yield 5.63 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 7.05 (1H, d, J=8.7 Hz), 7.24 (2H, d, J=8.7 Hz), 7.57 (1H, d, J=8.4 Hz), 7.70 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.82-7.93 (3H, m), 7.97 (1H, d, J=2.1 Hz), 8.25 (1H, dd, J=8.7 Hz, 2.7 Hz), 8.29 (1H, d, J=2.7 Hz), 9.96 (1H, s).

Reference Example 860 Production of ethyl {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzylamino}acetate

A solution of N-[2-(4-formylphenoxy)-5-pyridyl]-3,4-dichlorobenzamide (1.00 g, 2.58 mmol), glycine ethyl ester hydrochloride (0.400 g, 2.84 mmol) and sodium acetate (0.230 g, 2.84 mmol) in methanol (20 mL) was stirred for 30 minutes at 60° C. The reaction solution was cooled with ice, and then sodium cyanoborohydride (0.180 g, 2.84 mmol) was added. The resulting solution was stirred at the same temperature for 1 hour. To the reaction solution was added 5 M hydrochloric acid (2 mL) and concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2), to thereby yield 0.752 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.1 Hz), 3.43 (2H, s), 3.81 (2H, s), 4.20 (2H, q, J=7.1 Hz), 6.95 (1H, d, J=8.8 Hz), 7.09 (2H, d, J=8.5 Hz), 7.36 (2H, d, J=8.5 Hz), 7.57 (1H, d, J=8.3 Hz), 7.71 (1H, dd, J=2.1 Hz, 8.3 Hz), 7.84 (1H, s), 7.98 (1H, d, J=2.1 Hz), 8.18 (1H, dd, J=2.7 Hz, 8.8 Hz), 8.24 (1H, d, J=2.7 Hz).

Reference Example 861 Production of (acetyl{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzyl}amino)acetic acid

To a solution of ethyl {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzylamino}acetate (0.811 g, 1.59 mmol) in dichloromethane (5 mL) were added triethylamine (0.332 mL, 2.39 mmol) and acetyl chloride (0.136 mL, 1.91 mmol) at room temperature. The resulting solution was stirred for 1 hour at the same temperature. To the reaction solution was added water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.785 g of residue. This residue was dissolved in ethanol (5 mL). To the resulting solution was added 5 M aqueous sodium hydroxide (0.350 mL, 1.75 mmol) at room temperature and stirred at the same temperature for 14 hours. To the resulting reaction solution were added 5 N hydrochloric acid (0.400 mL) and water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.776 g of the title compound.

Appearance: White amorphous powder

¹H NMR (DMSO-d₆ at 375 K) δ 2.10 (3H, s), 4.02 (2H, s), 4.60 (2H, s), 7.03 (1H, d, J=8.8 Hz), 7.11 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 7.78 (1H, d, J=8.4 Hz), 7.97 (1H, dd, J=2.1 Hz, 8.4 Hz), 8.10-8.30 (2H, m), 8.53 (1H, d, J=2.6 Hz), 10.23 (1H, s).

Reference Example 862 Production of 1-(4-piperonylpiperazin-1-yl)-2-{methyl-[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}-ethanone

To a solution of {methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetic acid (0.93 g, 2.9 mmol) in DMF (40 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g, 3.5 mmol), 1-hydroxybenzotriazole monohydrate (0.54 g, 3.5 mmol), and 1-piperonylpiperazine (0.68 g, 3.08 mmol). The reaction mixture was stirred for 15 hours at room temperature under a nitrogen atmosphere. To the resulting solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→dichloromethane:methanol=100:1), to thereby yield 1.2 g of the title compound.

Appearance: Yellow powder

Melting point: 142-143° C.

The following compounds were produced in the same manner as in Reference Example 862.

TABLE 118

Reference Example No. R₃₇₁ R₃₇₂ Xa₂₈ Xa₂₉ ¹H NMR (CDCl₃) δppm 863 —CH₃ —CH₃ —CH₂— —CO— 2.09(3H, s), 3.04(3H, s), 3.22- 3.39(2H, m), 3.60-3.90(2H, m), 4.11(2H, s), 4.19-4.40(2H, m), 4.53(2H, s), 5.95(2H, s), 6.51- 6.62(2H, m), 6.68-6.80(3H, m), 6.92(1H, d, J = 8.6 Hz), 6.94(1H, d, J = 9.0 Hz), 8.42(1H, dd, J = 9.0 Hz, 2.6 Hz), 9.04(1H, d, J = 2.6 Hz). 864 —OCH₃ —C₂H₅ —CH₂— —CO— 1.21(3H, t, J = 6.7 Hz), 3.20- 3.33(2H, m), 3.46(2H, q, J = 6.7 Hz), 3.71(3H, s), 3.65-3.85(2H, m), 4.07 (2H, s), 4.29(2H, s), 4.52(2H, s), 5.96(2H, s), 6.23(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.39(1H, d, J = 2.6 Hz), 6.65-6.85(3H, m), 6.97(2H, d, J = 8.7 Hz), 8.41(1H, dd, J = 9.0 Hz, 2.8 Hz), 9.02(1H, d, J = 2.8 Hz). 865 —H —CH₃ —CH₂— —CH(CH₃)— 1.12-1.16(3H, m), 2.08-2.16(1H, m), 2.46-2.53(1H, m), 2.71-2.73(1H, m), 2.85-3.48(6H, m), 3.54-3.59(1H, m), 3.84-4.19(4H, m), 5.94(2H, s), 6.68- 6.74(4H, m), 6.85(1H, brs), 6.94(1H, d, J = 9.1 Hz), 7.01(2H, d, J = 8.9 Hz), 8.41(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, d, J = 2.8 Hz). 866 —H —C₂H₅ —CH₂— —CH(CH₃)— 1.13-1.28(6H, m), 2.08-2.16(1H, m), 2.47-2.50(1H, m), 2.71-2.75(1H, m), 2.86-3.35(3H, m), 3.41-3.49(2H, m), 3.58-3.62(1H, m), 3.85-4.16(4H, m), 5.94(2H, s), 6.67(2H, d, J = 9.1 Hz), 6.74(2H, brs), 6.85(1H, brs), 6.94(1H, d, J = 9.1 Hz), 6.99(2H, d, J = 9.1 Hz), 8.41(1H, dd, J = 9.1 Hz, 3.0 Hz), 9.05(1H, d, J = 2.5 Hz). 867 —H —CH₃ —CH(CH₃)— —CH₂— 1.29-1.40(8H, m), 1.96-2.06(1H, m), 2.17(1H, brs), 2.65-2.70(1H, m), 2.81-2.86(1H, m), 2.96-3.06(4H, m), 3.32-3.49(3H, m), 3.97-4.71(3H, m), 5.95(2H, s), 6.70(2H, d, J = 9.2 Hz), 6.74-6.75(2H, m), 6.87(1H, brs), 6.94(1H, dd, J = 9.1 Hz, 0.5 Hz), 7.01(2H, d, J = 9.2 Hz), 8.41(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, dd, J = 2.8 Hz, 0.5 Hz) 868 —H —C₂H₅ —CH(CH₃)— —CH₂— 1.20(3H, t, J = 7.1 Hz), 1.26- 1.40(3H, m), 1.98-2.05(1H, m), 2.16- 2.17(1H, m), 2.65-2.69(1H, m), 2.81- 2.85(1H, m), 3.02-3.56(6H, m), 4.03- 4.71(3H, m), 5.94(2H, s), 6.66(2H, d, J = 9.2 H), 6.74-6.75(2H, m), 6.87(1H, brs), 6.94(1H, dd, J = 9.1 Hz, 0.7 Hz), 6.99(2H, d, J = 9.1 Hz), 8.41(1H, dd, J = 9.1 Hz, 2.8 Hz), 8.05(1H, dd, J = 2.8 Hz, 0.7 Hz).

TABLE 119

Reference Example No. R₃₇₃ R₃₇₄ R₃₇₅ ¹H NMR (solvent) δppm or MS 869 —COOCH₃ —H —C₂H₅ MS 577(M⁺) 870 —OCH₃ —H —H ¹H NMR (DMSO-d₆) 2.32-2.40(4H, m), 3.42(2H, s), 3.50(4H, brs), 3.63(3H, s), 3.92(2H, d, J = 4.6 Hz), 5.65(1H, t, J = 4.8 Hz), 5.99(2H, s), 6.22(1H, dd, J = 8.6 Hz, 2.5 Hz), 6.51(1H, d, J = 2.5 Hz), 6.76(1H, dd, J = 7.9 Hz, 1.5 Hz), 6.84-6.91(3H, m), 7.07(1H, dd, J = 9.1 Hz, 0.5 Hz), 8.54(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.00(1H, dd, J = 2.8 Hz, 0.5 Hz). 871 —OCH₃ —H —CH₃ ¹H NMR (CDCl₃) 2.35-2.52(4H, m), 3.07(3H, s), 3.44(2H, s), 3.41-3.55(2H, m), 3.56-3.70(2H, m), 3.73(3H, s), 5.95(2H, s), 6.24(1H, dd, J = 8.8 Hz, 2.8 Hz), 6.35(1H, d, J = 2.8 Hz), 6.64-6.79(2H, m), 6.85(1H, s), 6.89-7.04(2H, m), 8.41(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03(1H, d, J = 2.8 Hz). 872 —OCH₃ —H —C₂H₅ ¹H NMR (CDCl₃) 1.22(3H, t, J = 7.0 Hz), 2.33- 2.52(4H, m), 3.49-3.58(6H, m), 3.59-3.69(2H, m), 3.72(3H, s), 4.06(2H, s), 5.95(2H, s), 6.22(1H, dd, J = 8.8 Hz, 2.7 Hz), 6.33(1H, d, J = 2.7 Hz), 6.69- 6.79(2H, m), 6.85(1H, s), 6.95(1H, d, J = 9.1 Hz), 6.96(1H, d, J = 8.8 Hz), 8.41(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04(1H, d, J = 2.8 Hz). 873 —CH₃ —H —H ¹H NMR (CDCl₃) 2.08(3H, s), 2.43-2.48(4H, m), 3.45-3.48(4H, m), 3.67-3.71(2H, m), 3.86(2H, d, J = 4.1 Hz), 4.93(1H, t, J = 4.1 Hz), 5.96(2H, s), 6.47- 6.52(2H, m), 6.71-6.78(2H, m), 6.86-6.96(3H, m), 8.44(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, d, J = 2.8 Hz). 874 —CH₃ —H —Ac ¹H NMR (CDCl₃) 1.98(3H, s), 2.16(3H, s), 2.32- 2.51(4H, m), 3.35-3.48(4H, m), 3.53-3.69(2H, m), 4.46(2H, s), 5.95(2H, s), 6.65-6.79(2H, m), 6.85(1H, s), 7.08(2H, d, J = 8.7 Hz), 7.27-7.34(1H, m), 7.35-7.42(1H, m), 8.51(1H, dd, J = 9.0 Hz, 2.8 Hz), 9.02(1H, dd, J = 2.8 Hz, 0.3 Hz). 875 —CH₃ —H —C₂H₅ ¹H NMR (CDCl₃) 1.20(3H, t, J = 7.1 Hz), 2.08(3H, s), 2.37-2.55(4H, m), 3.37-3.72(8H, m), 4.05(2H, s), 5.95(2H, s), 6.42-6.58(2H, m), 6.63-6.79(2H, m), 6.81-6.99(3H, m), 8.42(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, d, J = 2.8 Hz). 876 —CH₃ —H

¹H NMR (CDCl₃) 0.64-0.69(2H, m), 0.80-0.87(2H, m), 2.09(3H, s), 2.41-2.49(4H, m), 2.76-2.84(1H, m), 3.44(2H, s), 3.49-3.52(2H, m), 3.60-3.64(2H, m), 4.18(2H, s), 5.95(2H, s), 6.71-6.93(7H, m), 8.39-8.44(1H, m), 9.05-9.06(1H, m). 877 —CH₃ —CH₃ —CH₃ ¹H NMR (CDCl₃) 2.05(3H, s), 2.28(3H, s), 2.37- 2.43(4H, m), 2.72(3H, s), 3.42(2H, s), 3.52- 3.56(2H, m), 3.62-3.65(2H, m), 3.77(2H, s), 5.95(2H, s), 6.71-6.77(2H, m), 6.85-6.90(2H, m), 6.97-7.06(2H, m), 8.45(1H, dd, J = 9.1 Hz, 3.0 Hz), 9.04(1H, dd, J = 3.0 Hz, 0.5 Hz).

TABLE 120

Reference Example No. R₃₇₆ R₃₇₇ R₃₇₈ R₃₇₉ ¹H NMR (solvent) δppm or MS 878 —CH₃ —H —CH₃ —C₂H₅ MS 547(M⁺) 879 —F —H —H —H ¹H NMR (CDCl₃) 2.44-2.49(4H, m), 3.43-3.45(2H, m), 3.45(2H, s), 3.68-3.71(2H, m), 3.84(2H, d, J = 4.1 Hz), 5.12(1H, brs), 5.96(2H, s), 6.40-6.45(2H, m), 6.71-6.80(2H, m), 6.85(H, brs), 7.02(1H, t, J = 8.5 Hz), 7.05(1H, dd, J = 9.1 Hz, 0.5 Hz), 8.46(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02(1H, dd, J = 2.8 Hz, 0.7 Hz). 880 —F —H —H —CH₃ ¹H NMR (CDCl₃) 2.44(4H, brs), 3.06(3H, s), 3.45(2H, s), 3.45-3.47(2H, m), 3.62-3.64(2H, m), 4.11(2H, s), 5.95(2H, s), 6.40-6.51(2H, m), 6.71- 6.78(2H, m), 6.85(1H, brs), 7.04(1H, d, J = 9.1 Hz), 7.05(1H, t, J = 8.9 Hz), 8.46(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02(1H, d, J = 2.3 Hz) 881 —F —H —H —C₂H₅ ¹H NMR (CDCl₃) 1.22(3H, t, J = 7.2 Hz), 2.45(4H, brs), 3.40-3.49(4H, m), 3.45(2H, s), 3.65(2H, brs), 4.05(2H, s), 5.95(2H, s), 6.37-6.46(2H, m), 6.74- 6.75(2H, m), 6.86(1H, brs), 6.99-7.06(2H, m), 8.45(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03(1H, d, J = 2.5 Hz). 882 —F —H —H allyl ¹H NMR (CDCl₃) 2.46(4H, brs), 3.45(2H, s), 3.48(2H, brs), 3.65(2H, brs), 4.00(2H, d, J = 5.0 Hz), 4.07(2H, s), 5.19-5.29(2H, m), 5.82-5.94(1H, m), 5.95(2H, s), 6.37-6.47(2H, m), 6.71-6.78(2H, m), 6.86-6.87(1H, m), 6.98-7.05(2H, m), 8.45(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02(1H, dd, J = 2.8 Hz, 0.5 Hz) 883 —F —H —F —CH₃ ¹H NMR (CDCl₃) 2.33-2.49(4H, m), 2.99(3H, s), 3.43(2H, s), 3.37-3.50(2H, m), 3.51-3.68(2H, m), 4.10(2H, s), 5.95(2H, s), 6.69-6.78(2H, m), 6.81(1H, dd, J = 8.2 Hz, 12.1 Hz), 6.85(1H, d, J = 0.96 Hz), 6.90(1H, dd, J = 7.1 Hz, 12.8 Hz), 7.09(1H, d, J = 9.1 Hz), 8.49(1H, dd, J = 2.8 Hz, 9.0 Hz), 9.01(1H, d, J = 2.8 Hz). 884 —F —H —F —C₂H₅ ¹H NMR (CDCl₃) 1.17(3H, t, J = 7.1 Hz), 2.30- 2.52(4H, m), 3.35(2H, q, J = 7.1 Hz), 3.37-3.70(6H, m), 4.04(2H, s), 5.95(2H, s), 6.68-6.78(2H, m), 6.82(1H, dd, J = 8.0 Hz, 12.1 Hz), 6.83-6.88(1H, m), 6.91(1H, dd, J = 7.2 Hz, 12.5 Hz), 7.09(1H, d, J = 9.0 Hz), 8.49(1H, dd, J = 2.8 Hz, 9.0 Hz), 9.02(1H, d, J = 2.8 Hz). 885 —F —F —H —CH₃ ¹H NMR (DMSO-d₆) 2.20-2.45(4H, m), 2.91(3H, s), 3.34-3.53(6H, m), 4.31(2H, s), 5.98(2H, s), 6.47(2H, d, J = 11.8 Hz), 6.70-6.79(1H, m), 6.80-6.91(2H, m), 7.42(1H, d, J = 9.1 Hz), 8.64(1H, dd, J = 2.8 Hz, 9.1 Hz), 9.05(1H, d, J = 2.8 Hz). 886 —CH₃ —H —CH₃ —CH₃ MS 533(M⁺) 887 —CF₃ —H —H —C₂H₅ MS 587(M⁺) 888 —CF₃ —H —H —CH₃ MS 573(M⁺) 889 —H —F —F —CH₃ ¹H NMR (CDCl₃) 2.30-2.52(4H, m), 3.01(3H, s), 3.43(2H, s), 3.38-3.71(4H, m), 4.10(2H, s), 5.95(2H, s), 6.65-6.81(3H, m), 6.82-6.96(2H, m), 7.10(1H, d, J = 9.1 Hz) ,8.49(1H, dd, J = 2.8 Hz, 9.1 Hz), 9.01(1H, d, J = 2.8 Hz).

TABLE 121

Reference Example No. R₃₈₀ R₃₈₁ Xa₃₀ R₃₈₂ mp (° C.) or ¹H NMR (CDCl₃) δppm 890 —CH₃ —CH₃ —CH₂— benzyl ¹H NMR 2.12(3H, s), 2.40-2.55(4H, m), 3.04(3H, s), 3.45-3.55(2H, m), 3.54(2H, s), 3.60-3.70(2H, m), 4.10(2H, s), 6.50- 6.61(2H, m), 6.91(1H, d, J = 8.5 Hz), 6.92(1H, d, J = 9.1 Hz), 7.22-7.40(5H, m), 8.42(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, d, J = 2.8 Hz). 891 —CH₃ —C₂H₅ —CH₂— benzyl mp 134-136 892 —H —CH₃ —CH₂CH₂— piperonyl ¹H NMR 2.34-2.41(4H, m), 2.56-2.61 (2H, m), 2.97(3H, s), 3.39-3.42(4H, m), 3.60-3.64(2H, m), 3.71-3.76(2H, m), 5.94(2H, s), 6.72-6.76(5H, m), 6.83(1H, brs), 6.97(1H, d, J = 9.1 Hz), 7.02(1H, d, J = 9.1 Hz), 8.43(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04(1H, d, J = 2.8 Hz). 893 —CH₃ —CH₃ —CH(CH₃)— piperonyl ¹H NMR 1.31(3H, d, J = 6.6 Hz), 2.11 (3H, s), 2.17-2.49(4H, m), 2.78(3H, s), 3.31-3.56(3H, m), 3.39(2H, s), 3.77(1H, brs), 4.57(1H, q, J = 6.6 Hz), 5.94(2H, s), 6.60-6.63(2H, m), 6.68-6.75(2H, m), 6.83(1H, brs), 6.93-6.98(2H, m), 8.44(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, d, J = 2.8 Hz). 894 —H —CH₃ —CH(CH₃)— piperonyl ¹H NMR 1.32(3H, d, J = 6.6 Hz), 2.19- 2.50(4H, m), 2.80(3H, s), 3.30-3.56(3H, m), 3.32(2H, s), 3.78(1H, brs), 4.58(1H, q, J = 6.6 Hz) ,5.93(2H, s), 6.68-6.82(3H, m), 6.77(2H, d, J = 9.1 Hz), 6.98(1H, dd, J = 8.6 Hz, 0.5 Hz), 7.04(2H, d, J = 9.2 Hz), 8.44(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, dd, J = 2.8 Hz, 0.5 Hz). 895 —CH₃ —H —CO— piperonyl ¹H NMR 2.15(3H, s), 2.49-2.55(4H, m), 3.45(2H, s), 3.71-3.75(2H, m), 4.25- 4.28(2H, m), 5.96(2H, s), 6.75(2H, brs), 6.86(1H, brs), 7.04(1H, d, J = 9.1 Hz), 7.06(1H, d, J = 8.6 Hz), 7.49(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.61(1H, d, J = 2.5 Hz), 8.48(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02(1H, d, J = 2.8 Hz), 9.23(1H, brs). 896 —CH₃ —CH₃ —CO— piperonyl ¹H NMR 2.15(3H, s), 2.25-2.33(4H, m), 3.33-3.42(9H, m), 5.93(2H, s), 6.66- 6.79(3H, m), 7.04-7.21(4H, m), 8.51(1H, dd, J = 9.1 Hz, 2.8 Hz), 8.99(1H, dd, J = 2.8 Hz, 0.5 Hz).

TABLE 122

Reference Example No. R₃₈₃ ¹H NMR (CDCl₃) δppm or MS 897

MS 502(M⁺) 898

¹H NMR 2.44(4H, brs), 3.07(3H, s), 3.44(2H, s), 3.47-3.51(2H, m), 3.62-3.66(2H, m), 4.12(2H, s), 5.95(2H, s), 6.67-6.75(4H, m), 6.86(1H, s), 6.93-6.99(4H, m), 8.16(2H, d, J = 9.2 Hz). 899

¹H NMR 2.42(4H, t, J = 4.9 Hz), 3.04(3H, s), 3.42(2H, s), 3.44(2H, t, J = 4.9 Hz), 3.62(2H, t, J = 4.9 Hz), 4.11(2H, s), 5.95(2H, s), 6.42- 6.44(1H, m), 6.50-6.51(1H, m), 6.54-6.58(1H, m), 6.70-6.77(2H, m), 6.84(1H, m), 6.96(1H, d, J = 9.1 Hz), 7.24-7.30(1H, m), 8.43(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.08(1H, d, J = 2.8 Hz). 900

¹H NMR 2.44(4H, brs), 3.44(2H, s), 3.55(2H, brs), 3.73(2H, brs), 5.95(2H, s), 6.74(2H, s), 6.85(1H, s), 6.86(1H, d, J = 8.6 Hz), 7.14(2H, d, J = 8.6 Hz), 7.46(2H, d, J = 8.6 Hz), 7.79(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.22(1H, d, J = 2.5 Hz). 901

MS 508(M⁺) 902

MS 587(M⁺) 903

¹H NMR 2.31-2.50(4H, m), 2.96(3H, s), 3.42(2H, s), 3.40-3.52(2H, m), 3.53-3.67(2H, m), 4.05(2H, s), 5.95(2H, s), 6.65-6.95(6H, m), 7.77(1H, dd, J = 2.5 Hz, 8.7 Hz), 8.16(1H, dd, J = 0.5 Hz, 2.5 Hz).

TABLE 123

Reference Example No. R₃₈₄ ¹H NMR (CDCl₃) δppm 904 —H 2.29-2.34(4H, m), 3.15(3H, s), 3.34-3.43(6H, m), 4.63(2H, s), 5.98(2H, s), 6.72-6.76(1H, m), 6.83-6.86(2H, m), 7.27(2H, d, J = 8.9 Hz), 7.31(1H, d, J = 9.3 Hz), 7.54(2H, d, J = 8.9 Hz), 8.64(1H, dd, J = 9.2 Hz, 2.8 Hz), 9.05(1H, d, J = 2.8 Hz). 905 —CH₃ 2.15(3H, s), 2.42-2.43(4H, m), 3.22(3H, s), 3.39-3.41(2H, m), 3.43(2H, s), 3.61-3.63(2H, m), 4.56(2H, s), 5.94(2H, s), 6.70-6.77(2H, m), 6.84(1H, brs), 7.06(1H, d, J = 8.2 Hz), 7.07(1H, d, J = 9.1 Hz), 7.48- 7.52(2H, m), 8.49(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01(2H, d, J = 2.8 Hz). 906 —OCH₃ 2.42-2.46(4H, m), 3.24(3H, s), 3.40(2H, brs), 3.43(2H, s), 3.63(2H, brs), 3.74(3H, s), 4.58(2H, s), 5.94(2H, s), 6.70-6.77(2H, m), 6.84 (1H, s), 7.06-7.14(2H, m), 7.23-7.28(1H, m), 7.32(1H, d, J = 2.3 Hz), 8.47(1H, dd, J = 9.1 Hz, 2.8 Hz), 8.98(1H, d, J = 2.8 Hz).

TABLE 124

Reference Example No. R₃₈₅ ¹H NMR (CDCl₃) δppm 907 piperonyl 1.33-1.46(2H, m), 1.86-2.00(3H, m), 2.10(3H, s), 2.29(2H, d, J = 6.8 Hz), 2.39-2.43(4H, m), 2.75(2H, t, J = 12.2 Hz), 3.40-3.48(4H, m), 3.62-3.66(4H, m), 5.94(2H, s), 6.73-6.85(5H, m), 6.91-6.96(2H, m), 8.43(1H, dd, J = 9.1 Hz, 3.0 Hz), 9.04(1H, d, J = 2.8 Hz). 908 benzyl 1.35-1.46(2H, m), 1.86-2.00(3H, m), 2.10(3H, s), 2.29(2H, d, J = 6.8 Hz), 2.41-2.45(4H, m), 2.75(2H, t, J = 12.2 Hz), 3.47-3.53(4H, m), 3.61-3.65(4H, m), 6.79-6.96(4H, m), 7.24-7.33(5H, m), 8.43(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, d, J = 2.8 Hz).

Reference Example 909 Production of (4-benzylpiperazin-1-yl){4-[methyl(5-nitropyridin-2-yl)amino]phenyl}ethanone

To a solution of 4-[methyl-(5-nitropyridin-2-yl)amino]benzoic acid (0.800 g, 2.93 mmol) and 1-benzylpiperazine (0.542 g, 3.08 mmol) in DMF (15 mL) were added triethylamine (1.02 mL, 7.32 mmol) and diethyl cyanophosphonate (0.593 mL, 3.52 mmol), and the resulting solution was stirred for 3 hours. To the resulting reaction solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield 1.25 g of the title compound.

Appearance: Yellow amorphous powder

¹H NMR (CDCl₃) δ 2.25-2.65 (4H, m), 3.49 (2H, brs), 3.56 (2H, s), 3.57 (3H, s), 3.81 (2H, brs), 6.43 (1H, d, J=9.5 Hz), 7.25-7.35 (7H, m), 7.53 (2H, d, J=8.4 Hz), 8.06 (1H, dd, J=2.8 Hz, 9.5 Hz), 9.12 (1H, d, J=2.8 Hz).

The following compounds were produced in the same manner as in Reference Example 909.

TABLE 125

Reference Example No. Xa₃₁ R₃₈₆ Xa₃₂ M ¹H NMR (DMSO-d₆) δppm 910 —NH— —H —CH₂— 1 2.20-2.30(4H, m), 2.59(2H, t, J = 7.3 Hz), 2.78(2H, t, J = 7.3 Hz), 3.35(2H, s), 3.36- 3.45(4H, m), 5.98(2H, s), 6.72(1H, dd, J = 1.3 Hz, 7.9 Hz), 6.80-6.90(3H, m), 7.21(2H, d, J = 8.4 Hz), 7.57(2H, d, J = 8.4 Hz), 8.26(1H, dd, J = 2.9 Hz, 9.3 Hz), 9.01(1H, d, J = 2.9 Hz), 10.06(1H, s). 911 —O— —H —NH— 1 2.32(2H, brs), 2.39(2H, brs), 3.41(2H, s), 3.50(4H, brs), 3.91(2H, d, J = 5.2 Hz), 5.68(1H, t, J = 5.2 Hz), 5.99(2H, s), 6.70(2H, d, J = 8.9 Hz), 6.74-6.77(1H, m), 6.83-6.88(2H, m), 6.94(2H, d, J = 8.9 Hz), 7.11(1H, d, J = 9.1 Hz), 8.56(1H, dd, J = 2.9 Hz, 9.1 Hz), 9.02(1H, d, J = 2.9 Hz). 912 —O— —OCH₃ —NH— 2 2.48(2H, brs0, 2.49(2H, brs), 3.89(2H, s), 3.50(4H, brs), 3.63(3H, s), 3.92(2H, d, J = 4.8 Hz), 4.22(4H, s), 5.65(1H, brt), 6.22(1H, dd, J = 8.6 Hz, 2.5 Hz), 6.51(1H, d, J = 2.5 Hz), 6.73- 6.81(3H, m), 6.89(1H, d, J = 8.6 Hz), 7.07(1H, d, J = 9.1 Hz), 8.54(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.00(1H, d, J = 2.8 Hz).

Reference Example 913 Production of N-[4-(5-nitropyridin-2-yloxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]acetamide

To a solution of ethyl (acetyl [4-(5-nitropyridin-2-yloxy)phenyl]amino]acetate (2.30 g, 6.40 mmol) in ethanol (50 mL) was added 5 M aqueous sodium hydroxide (1.92 mL, 9.60 mmol), and the resulting solution was stirred at room temperature for 30 minutes. To this reaction solution were added 5 M hydrochloric acid (2 mL) and water, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 1.68 g of an oil. To a solution of this oil in DMF (10 mL) were added 1-piperonylpiperazine (1.29 g, 5.86 mmol), triethylamine (1.85 mL, 13.3 mmol) and diethyl cyanophosphonate (1.07 mL, 6.36 mmol), and the resulting solution was stirred for 1 hour at room temperature. To this reaction solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), to thereby yield 2.21 g of the title compound.

Appearance: Yellow amorphous powder

¹H NMR (CDCl₃) δ 1.98 (3H, s), 2.40-2.50 (4H, m), 3.40-3.45 (4H, m), 3.62 (2H, brs), 4.48 (2H, s), 5.94 (2H, s), 6.70-6.76 (2H, m), 6.85 (1H, s), 7.09 (1H, d, J=9.1 Hz), 7.20 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.7 Hz), 8.51 (1H, dd, J=2.8 Hz, 9.1 Hz), 9.04 (1H, d, J=2.8 Hz).

The following compounds were produced in the same manner as in Reference Example 913.

TABLE 126

Reference Example No. R₃₈₇ R₃₈₈ MS (M⁺) 914 —CH₃ —CH₃ 587 915 —H —C₂H₅ 587

Reference Example 916 Production of 3-[3-methoxy-4-(5-nitropyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propan-1-one

3-[3-methoxy-4-(5-nitropyridin-2-yloxy)phenyl]propionic acid (3.18 g, 10 mmol) was dissolved in dichloromethane (30 mL). To the resulting solution were added thionyl chloride (0.88 mL, 12 mmol) and DMF (1 drop), and refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 mL). To the resulting solution were added triethylamine (1.67 mL, 12 mmol) and a solution of 1-piperonylpiperazine (2.20 g, 10 mmol) in dichloromethane (30 mL) under ice cooling, and the resulting solution was stirred for 1 hour at 0° C. The resulting reaction solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 4.95 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 2.33-2.42 (4H, m), 2.63-2.69 (2H, m), 2.97-3.03 (2H, m), 3.42 (4H, brs), 3.62-3.66 (2H, m), 3.74 (3H, s), 5.95 (2H, s), 6.73-6.75 (2H, m), 6.85-6.90 (3H, m), 7.04 (1H, d, J=9.1 Hz), 7.06 (1H, d, J=7.9 Hz), 8.45 (1H, dd, J=9.1 Hz, 2.8 Hz), 9.01 (1H, d, J=2.8 Hz).

The following compound was produced in the same manner as in Reference Example 916.

Reference Example 917 6-Chloro-N-(4-trifluoromethylphenyl)nicotinamide

¹H NMR (DMSO-d₆) δ7.74 (1H, d, J=8.4 Hz), 7.76 (2H, d, J=8.7 Hz), 8.00 (2H, d, J=8.7 Hz), 8.38 (1H, dd, J=8.7 Hz, 2.5 Hz), 8.97 (1H, d, J=2.5 Hz), 10.80 (1H, brs).

Reference Example 918 Production of 3-{3-methoxy-4-[methyl(5-nitropyridin-2-yl)amino]phenyl}-1-(4-piperonylpiperazin-1-yl)propan-1-one

To a solution of ethyl 3-{3-methoxy-4-[methyl-(5-nitropyridin-2-yl)amino]phenyl}propionate (3.85 g, 11 mmol) in ethanol (80 mL) was added 2 N aqueous sodium hydroxide (6.4 mL, 13 mmol), and the resulting solution was stirred at room temperature for 2.5 hours. To the resulting reaction solution was added 6 N hydrochloric acid (2.2 mL, 13 mmol), and the solvent was removed under reduced pressure. To the residue were added THF (80 mL) and N,N′-carbonyldiimidazole (2.08 g, 13 mmol), and the resulting solution was stirred at room temperature for 3 hours. To the resulting reaction solution were added 1-piperonylpiperazine (2.60 g, 12 mmol) and DMF (40 mL), and stirred at room temperature for 21 hours. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield 4.59 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 2.36-2.43 (4H, m), 2.64-2.70 (2H, m), 2.99-3.05 (2H, m), 3.42-3.46 (7H, m), 3.63-3.67 (2H, m), 3.77 (3H, s), 5.95 (2H, s), 6.12 (1H, brd, J=9.1 Hz), 6.70-6.77 (2H, m), 6.85-6.90 (3H, m), 7.12 (1H, d, J=8.1 Hz), 7.97-8.01 (1H, m), 9.11 (1H, d, J=2.6 Hz).

Reference Example 919 Production of 5-{methyl[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl]amino}-2-(5-nitropyridin-2-yloxy)benzonitrile

To a solution of t-butyl 2-((3-cyano-4-(5-nitropyridin-2-yloxy)phenyl)(methyl)amino)acetate (1.2 g, 3.1 mmol) in dichloromethane (12 mL) was added trifluoroacetic acid (12 mL), and the resulting reaction solution was stirred at room temperature for 5 hours. The solvent was evaporated, and water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield crude 2-((3-cyano-4-(5-nitropyridin-2-yloxy)phenyl)(methyl)amino)acetic acid. To a solution of this compound in DMF (24 mL) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (659 mg, 3.4 mmol), 1-hydroxybenzotriazole monohydrate (526 mg, 3.4 mmol) and 1-piperonylpiperazine (757 mg, 3.4 mmol), and the resulting reaction solution was stirred for 8 hours at room temperature. Water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was then washed with, in order, saturated aqueous sodium bicarbonate solution, water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate), to thereby yield 412 g of the title compound.

Appearance: Yellow amorphous powder

¹H NMR (CDCl₃) δ 2.40-2.55 (4H, m), 3.09 (3H, s), 3.45-3.50 (4H, m), 3.55-3.70 (2H, m), 4.14 (2H, s), 5.95 (2H, s), 6.70-6.80 (2H, m), 6.80-6.95 (3H, m), 7.10-7.20 (2H, m), 8.50 (1H, dd, J=9.1 Hz, 2.8 Hz), 8.99 (1H, d, J=2.8 Hz).

Reference Example 920 Production of 2-{(2,3-difluoro-4-t-butoxycarbonylamino)phenoxy}-5-nitropyridine

To a solution of {2,3-difluoro-4-(5-nitropyridin-2-yloxy)}benzoic acid (1.22 g, 4.1 mmol) in t-butanol (50 mL) were added diphenylphosphorylazide (0.98 mL, 4.5 mmol) and triethylamine (0.63 mL, 4.5 mmol), and the resulting solution was refluxed for 4 hours under a nitrogen atmosphere. After cooling, water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1), to thereby yield 1.2 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.54 (9H, s), 6.59-6.78 (1H, m), 6.90-7.04 (1H, m), 7.13 (1H, d, J=9.0 Hz), 7.84-8.02 (1H, m), 8.51 (1H, dd, J=2.8 Hz, 9.0 Hz), 8.99 (1H, d, J=2.8 Hz).

Reference Example 921 Production of 3,4-dichloro-N-[3-fluoro-4-(4-formylphenoxy)phenyl]benzamide

3,4-Dichloro-N-[4-(4-[1,3]dioxsolane-2-ylphenoxy)-3-fluorophenyl]benzamide (17.4 g, 38.9 mmol) was added to 80% acetic acid, and the resulting solution was stirred for 1.5 hours at 80° C. The reaction solution was concentrated under reduced pressure, wherein the obtained residue was recrystallized from 80% ethanol to thereby yield 12.8 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (DMSO-d₆) δ 7.13 (2H, d, J=8.6 Hz), 3.40 (1H, t, J=9.0 Hz), 7.63 (1H, d, J=9.0 Hz), 7.85 (1H, d, J=8.4 Hz), 7.90-8.00 (4H, m), 8.22 (1H, d, J=1.9 Hz), 9.93 (1H, s), 10.67 (1H, s).

Reference Example 922 Production of N-(6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride

t-Butyl {4-(5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}carbamate (4.31 g, 9.09 mmol) was dissolved in a mixed solution of chloroform-methanol-ethyl acetate. The resulting solution was concentrated to a volume of about 20 mL. To the residue solution was added a solution of 4 N hydrogen chloride in ethyl acetate (70 mL), and left to cool for 2 hours at room temperature. The precipitated white powder was filtered, and washed with ethyl acetate, to thereby yield 4.04 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 5.20 (2H, brs), 7.14 (1H, d, J=8.5 Hz), 7.25 (2H, d, J=8.9 Hz), 7.42 (2H, d, J=8.9 Hz), 7.84 (1H, d, J=8.5 Hz), 7.97 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.24 (1H, dd, S=8.5 Hz, 2.6 Hz), 8.25 (1H, d, J=2.0 Hz), 8.51 (1H, d, J=2.6 Hz), 10.65 (1H, s).

The following compounds were produced in the same manner as in Reference Example 922.

TABLE 127

Reference Example ¹H NMR (CDCl₃) δppm or No. R₃₈₉ R₃₉₀ R₃₉₁ R₃₉₂ R₃₉₃ MS 923 —F —H —F —H —CH₃ ¹H NMR 2.83(3H, d, J = 5.2 Hz), 3.90-4.05(1H, m), 6.18- 6.27(2H, m), 7.15(1H, d, J = 9.0 Hz), 8.49(1H, dd, J = 2.8 Hz, 9.0 Hz), 9.02(1H, d, J = 2.8 Hz). 924 —F —F —H —H —CH₃ ¹H NMR 2.92(3H, d, J = 3.8 Hz), 3.90-4.16(1H, m), 6.46(1H, td, J = 2.2 Hz, 8.8 Hz), 6.89(1H, td, J = 2.4 Hz, 7.8 Hz), 7.08(1H, d, J = 9.0 Hz), 8.49(1H, dd, J = 2.8 Hz, 9.0 Hz), 9.02(1H, d, J = 2.8 Hz). 925 —COOCH₃ —H —H —CH₂COOH —C₂H₅ MS 375(M⁺)

Reference Example 926 Production of 4-(tetrahydropyran-2-yloxy)benzylamine

To a solution of lithium aluminum hydride (2.66 g, 70 mmol) in THF (200 mL) was added dropwise under ice cooling a solution of 4-(tetrahydropyran-2-yloxy)benzonitrile in THF (70 mL). The resulting solution was then refluxed for 1 hour. The resulting reaction solution was again cooled with ice, and then to the solution was added dropwise, in order, water (2.66 mL), 1 N aqueous sodium hydroxide (2.66 mL) and water (7.98 mL). Insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, after which the residue was purified by silica gel column chromatography (chloroform:methanol=7:1), to thereby yield 11.41 g of the title compound.

Appearance: Colorless oil

¹H NMR (CDCl₃) δ 1.56 (2H, s), 1.45-1.78 (3H, m), 1.78-2.12 (3H, m), 3.53-3.66 (1H, m), 3.80 (2H, s), 3.84-3.99 (1H, m), 5.41 (1H, t, J=3.2 Hz), 7.02 (2H, d, 8.7 Hz), 7.22 (2H, d, J=8.7 Hz).

Reference Example 927 Production of 4-(2-fluoro-4-nitrophenoxy)phenylamine hydrochloride

N-[4-(2-fluoro-4-nitrophenoxy)phenyl]-acetamide (1.00 g, 3.45 mmol) was added to 6 M hydrochloric acid (10 mL), and the resulting solution was refluxed for 2 hours. The resulting reaction solution was concentrated under reduced pressure, to thereby yield 0.910 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (DMSO-d₆) δ 3.40-4.00 (2H, m), 7.18 (1H, t, J=8.7 Hz), 7.24 (2H, d, J=8.9 Hz), 7.32 (2H, d, J=8.9 Hz), 8.10 (1H, ddd, J=1.4 Hz, 2.6 Hz, 8.9 Hz), 8.35 (1H, dd, J=2.6 Hz, 10.8 Hz).

Reference Example 928 Production of {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}carbamate phenyl ester

To a suspension of N-[6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride (700 mg, 1.57 mmol) in THF (20 mL) was added triethylamine (1.1 mL, 7.89 mmol). To the resulting solution was then added dropwise phenyl chlorocarbonate (0.39 mL, 3.14 mmol) under ice cooling. The resulting reaction solution was stirred for 1 hour at room temperature. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, whereupon the residue solidified into a powder. The powder was filtered, and washed with diethyl ether, to thereby yield 470 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 7.04 (1H, d, J=8.9 Hz), 7.11 (2H, d, J=8.9 Hz), 7.19-7.31 (3H, m), 7.38-7.49 (2H, m), 7.53 (2H, d, J=8.0 Hz), 7.84 (1H, d, J=8.4 Hz), 7.95 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.18 (1H, dd, J=8.9 Hz, 2.2 Hz), 8.22 (1H, d, J=2.0 Hz), 8.47 (1H, d, J=2.2 Hz), 10.26 (1H, s), 10.54 (1H, s).

The following compounds were produced in the same manner as in Reference Example 928.

TABLE 128

Reference Example No. R₃₉₄ M ¹H NMR (solvent) δppm 929

0 (DMSO-d₆) 7.08(1H, t, J = 8.7 Hz), 7.15-7.30(5H, m), 7.35-7.50(2H, m), 7.60(2H, d, J = 8.9 Hz), 8.07(1H, dd, J = 1.1 Hz, 9.0 Hz), 8.31(1H, dd, J = 2.6 Hz, 10.9 Hz), 10.36(1H, s). 930

0 (CDCl₃) 1.50-1.80(3H, m), 1.80-2.15(3H, m), 3.55- 3.67(1H, m), 3.85-4.00(1H, m), 5.37(1H, t, J = 3.3 Hz), 6.83(1H, brs), 7.03(2H, d, J = 9.1 Hz), 7.14-7.30(3H, m), 7.30-7.47(4H, m). 931

1 (CDCl₃) 1.50-1.79(3H, m), 1.79-2.15(3H, m), 3.55- 3.60(1H, m), 3.82-4.00(1H, m), 3.39(2H, d, J = 6.0 Hz), 5.26(1H, brs), 5.42(1H, t, J = 3.1 Hz), 7.05(2H, d, J = 8.7 Hz), 7.27(2H, d, J = 8.7 Hz), 7.10-7.40(5H, m).

Reference Example 932 Production of 4-piperonylpiperazine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)phenyl]amide

To a solution of [4-(2-fluoro-4-nitrophenoxy)phenyl]carbamate phenyl ester (0.700 g, 1.90 mmol) in DMF (15 mL) was added 1-piperonylpiperazine (0.460 g, 2.09 mmol), and the resulting solution was stirred for 2 hours at room temperature. water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.939 g of the title compound.

Appearance: Yellow oil

¹H NMR (DMSO-d₆) δ 2.30-2.40 (4H, m), 3.35-3.50 (6H, m), 6.00 (2H, s), 6.70-6.90 (2H, m), 7.00-7.15 (2H, m), 7.55 (2H, d, J=9.1 Hz), 8.05-8.10 (1H, m), 8.30 (1H, dd, J=2.8 Hz, 10.9 Hz), 9.31 (1H, s).

The following compounds were produced in the same manner as in Reference Example 932.

Reference Example 933 Ethyl 3-(4-{5-[(3-(3,4-dichlorophenyl)-3-ethylureido]-pyridin-2-yloxy}phenyl)propionate

MS 501 (M⁺).

TABLE 129

Reference Example No. R₃₉₅ M ¹H NMR (CDCl₃) δppm 934 benzyl 0 1.50-1.87(3H, m), 1.87-2.15(3H, m), 2.48(4H, t, J = 5.1 Hz), 3.48(4H, t, J = 5.1 Hz), 3.54(2H, s), 3.50-3.65(1H, m), 3.85- 4.00(1H, m), 5.34(1H, t, J = 3.2 Hz), 6.21(1H, brs), 6.98(2H, d, J = 8.9 Hz), 7.22(2H, d, J = 8.9 Hz), 7.25-7.38(5H, m). 935 piperonyl 1 1.48-1.77(3H, m), 1.77-2.11(3H, m), 2.40(4H, t, J = 5.0 Hz), 3.36(4H, t, J = 5.0 Hz), 3.41(2H, s), 3.50-3.67(1H, m), 3.81- 3.96(1H, m), 4.34(2H, d, J = 5.1 Hz), 4.61(1H, t, J = 5.1 Hz), 5.40(1H, t, J = 3.2 Hz), 5.94(2H, s), 6.74(2H, s), 6.84(1H, s), 7.00(2H, d, J = 8.6 Hz), 7.22(2H, d, J = 8.6 Hz).

Reference Example 936 Production of 4-piperonylpiperazine-1-carboxylic acid 4-hydroxybenzylamide

To a solution of 4-piperonylpiperazine-1-carboxylic acid 4-(tetrahydropyran-2-yloxy)benzylamide (1.1 g, 2.43 mmol) in methanol (50 mL) was added p-toluenesulfonic acid monohydrate (1.0 g, 5.26 mmol), and the resulting solution was stirred for 1 hour at room temperature. The resulting reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 330 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.41 (4H, t, J=5.0 Hz), 3.37 (4H, t, J=5.0 Hz), 3.42 (2H, s), 4.32 (2H, d, J=5.2 Hz), 4.68 (1H, t, J=5.2 Hz), 5.94 (2H, s), 6.15 (1H, brs), 6.70-6.80 (2H, m), 6.75 (2H, d, J=8.6 Hz), 6.84 (1H, s), 7.13 (2H, d, J=8.6 Hz).

The following compound was produced in the same manner as in Reference Example 936.

Reference Example 937 4-Benzylpiperazine-1-carboxylic acid (4-hydroxyphenyl)methylamide hydrochloride

¹H NMR (DMSO-d₆) δ 2.69-2.91 (2H, m), 3.03 (3H, s), 2.92-3.23 (4H, m), 3.68 (2H, d, J=13. Hz), 4.26 (2H, s), 6.75 (2H, d, J=8.7 Hz), 6.98 (2H, d, J=8.7 Hz), 7.45 (3H, brs), 7.54 (2H, brs), 9.52 (1H, s).

Reference Example 938 Production of 3,4-dichloro-N-{6-[(4-(3-hydroxypropyl)phenoxy]pyridin-3-yl}benzamide

To 2-{4-[3-(t-butyldimethylsilanyloxy)propyl]phenoxy}-5-nitropyridine (950 mg, 1.8 mmol) were added acetic acid (10 mL) and water (5 mL), and the resulting solution was stirred for 1 hour at room temperature. The resulting reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 520 mg of the title compound.

Appearance: White prism

¹H NMR (DMSO-d₆) δ 1.70-1.78 (2H, m), 2.59-2.65 (2H, m), 3.32-3.47 (2H, m), 4.46-4.49 (1H, m), 7.00-7.05 (3H, m), 7.23 (2H, d, J=8.2 Hz), 7.84 (1H, d, J=8.2 Hz), 7.95 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.16-8.22 (2H, m), 8.48 (1H, d, J=2.6 Hz), 10.54 (1H, s).

The following compound was produced in the same manner as in Reference Example 938.

Reference Example 939 3,4-Dichloro-N-{6-[4-(2-hydroxyethyl)phenoxy]pyridin-3-yl}benzamide

¹H NMR (DMSO-d₆) δ 2.73 (2H, t, J=6.9 Hz), 3.59-3.66 (2H, m), 4.65 (1H, t, J=5.3 Hz), 7.00-7.06 (3H, m), 7.25 (2H, d, J=8.3 Hz), 7.84 (1H, d, J=8.3 Hz), 7.95 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.16-8.23 (2H, m), 8.47 (1H, d, J=2.6 Hz), 10.54 (1H, s).

Reference Example 940 Production of 3,4-dichloro-N-{6-[4-(5-hydroxypentyl)phenoxy]pyridin-3-yl}benzamide

To a solution of ethyl 5-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}pentanoate (8.79 g, 18.0 mmol) in THF (140 mL) was added sodium borohydride (3.14 g, 144 mmol), and the resulting solution was refluxed for 3 hours under a nitrogen atmosphere. The resulting reaction solution was cooled with ice, and treated with 1 N hydrochloric acid. The resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2), to thereby yield 7.07 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.25-1.75 (7H, m), 2.62 (2H, t, J=7.6 Hz), 3.65 (2H, t, J=6.6 Hz), 6.92 (1H, d, J=8.5 Hz), 7.02 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.69 (1H, dd, J=8.5 Hz, 2.0 Hz), 7.93 (1H, s), 7.97 (1H, d, J=2.0 Hz), 8.15 (1H, dd, J=8.5 Hz, 2.5 Hz), 8.22 (1H, d, J=2.5 Hz).

The following compounds were produced in the same manner as in Reference Example 940.

TABLE 130

Reference Example No. M mp (° C.) 941 1 162-163 942 2 104-105 943 3 111-113 944 4 102-104

TABLE 131

Reference Example No. R₃₉₆ R₃₉₇ M ¹H NMR (DMSO-d₆) δppm 945 —Cl —Cl 1 4.49(2H, d, J = 5.6 Hz), 5.17(1H, brs), 7.03-7.08(3H, m), 7.35(2H, d, J = 8.6 Hz), 7.84(1H, d, J = 8.6 Hz), 7.93- 7.97(1H, m), 8.17-8.22(2H, m), 8.47(1H, d, J = 2.6 Hz), 10.53(1H, s). 946 —CF₃ —H 1 4.50(2H, d, J = 5.7 Hz), 5.18(1H, t, J = 5.7 Hz), 7.04- 7.09(3H, m), 7.35(2H, d, J = 8.4 Hz), 7.93(2H, d, J = 8.4 Hz), 8.15-8.24(3H, m), 8.50(1H, d, J = 2.7 Hz), 10.61(1H, s). 947 —Cl —Cl 4 1.35-1.70(4H, m), 2.59(2H, t, J = 7.5 Hz), 3.42(2H, q, J = 6.0 Hz), 4.37(1H, t, J = 5.5 Hz), 7.02(2H, d, J = 8.2 Hz), 7.04(1H, d, J = 8.6 Hz), 7.22(2H, d, J = 8.2 Hz), 7.84(1H, d, J = 8.2 Hz), 7.94(1H, dd, J = 8.2 Hz, 2.0 Hz), 8.18(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, d, J = 2.0 Hz), 8.47(1H, d, J = 2.6 Hz), 10.53(1H, s).

Reference Example 948 Production of 4-cyano-N-[6-(4-hydroxymethylphenoxy)pyridin-3-yl]benzamide

A suspension of 4-(5-(4-cyanobenzoylamino)pyridin-2-yloxy]benzoic acid (1.80 g, 5.01 mmol) in THF (20 mL) was cooled with ice-common salt, and to the solution was added triethylamine (0.77 mL, 5.51 mmol), and then ethyl chlorformate (0.53 mL, 5.51 mmol). The resulting solution was stirred at room temperature. Thirty minutes later, the reaction solution was filtered and insoluble matter was removed. The resulting filtrate was poured while stirring under ice cooling into an aqueous solution of sodium borohydride (0.95 g, 25.05 mmol) in 80% methanol (40 mL). After stirring for 30 minutes at room temperature, water (200 mL) was added to the reaction solution. The obtained mixture was extracted with ethyl acetate (200 mL). The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from a mixed solution of ethyl acetate-n-hexane, to thereby yield 1.26 g of the title compound.

Appearance: Slightly yellow powder

¹H NMR (DMSO-d₆) δ 4.50 (2H, d, J=5.3 Hz), 5.19 (1H, t, J=5.6 Hz), 7.04-7.09 (3H, m), 7.35 (2H, d, J=8.6 Hz), 8.04 (2H, d, J=8.9 Hz), 8.12 (2H, d, J=8.6 Hz), 8.21 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.49 (1H, d, J=2.3 Hz), 11.63 (1H, s).

The following compounds were produced in the same manner as in Reference Example 948.

Reference Example 949 4-Chloro-N-[6-(4-hydroxymethylphenoxy)pyridin-3-yl]benzamide

¹H NMR (DMSO-d₆) δ 4.50 (2H, d, J=5.3 Hz), 5.18 (1H, t, J=5.6 Hz), 7.03-7.08 (3H, m), 7.35 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz), 8.00 (2H, d, J=8.6 Hz), 8.20 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.48 (1H, d, J=2.3 Hz), 10.46 (1H, s).

TABLE 132

Reference Example No. R₃₉₈ R₃₉₉ ¹H NMR (CDCl₃) δ ppm 950 —H —NO₂ 4.71 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.9 Hz), 7.83 (1H, dd, J = 8.3 Hz, 2.3 Hz), 8.19 (1H, d, J = 2.5 Hz), 8.27 (2H, d, J = 8.9 Hz). 951 —CH₃ —NO₂ 2.30 (4H, brs), 4.67 (2H, s), 7.02 (1H, d, J = 8.41 Hz), 7.12 (1H, d, J = 8.90 Hz), 7.80 (1H, dd, J = 8.41 Hz, 2.47 Hz), 8.05-8.17 (3H, m). 952 —H

2.45 (4H, brs), 3.45 (2H, s), 3.57 (2H, brs), 3.69 (2H, brs), 4.67 (2H, s), 5.95 (2H, s), 6.74-6.77 (2H, m), 6.85 (1H, s), 6.94 (1H, d, J = 8.4 Hz), 7.14 (2H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 2.5 Hz, 8.4 Hz), 8.16 (1H, d, J = 2.5 Hz). 953 —H

1.96 (1H, brs), 2.40-2.44 (4H, m), 3.02 (3H, s), 3.43 (2H, brs), 3.47-3.49 (2H, m), 3.62 (2H, brs), 4.07 (2H, s), 4.62 (2H, s), 5.94 (2H, s), 6.68-6.77 (4H, m), 6.81 (1H, d, J = 8.6 Hz), 6.85 (1H, brs), 6.99 (2H, d, J = 9.2 Hz), 7.66 (1H, dd, J = 8.4 Hz, 2.5 Hz), 8.13 (1H, d, J = 2.5 Hz). 954 —H

1.75-2.01 (1H, m), 2.22-2.50 (4H, m), 2.51-2.70 (2H, m), 2.88-3.07 (2H, m), 3.30-3.51 (4H, m), 3.52-3.78 (2H, m), 4.67 (2H, s), 5.96 (2H, s), 6.69-6.81 (2H, m), 6.83-6.88 (1H, m), 6.91 (1H, d, J = 8.4 Hz), 7.01-7.11 (2H, m), 7.19-7.29 (2H, m), 7.74 (1H, dd, J = 2.5 Hz, 8.4 Hz), 8.16 (1H, dd, J = 0.5 Hz, 2.5 Hz).

Reference Example 955 Production of 2-[4-(1-bromoethyl)phenoxy]-5-nitropyridine

2-(4-ethylphenoxy)-5-nitropyridine (7.33 g, 30 mmol) was dissolved in carbon tetrachloride (100 mL), and to the resulting solution were added N-bromosuccimide (5.34 g, 30 mmol) and benzoyl peroxide (0.73 g, 3 mmol). This solution was refluxed overnight under a nitrogen atmosphere. The reaction solution was allowed to cool, after which insoluble matter was removed by filtration. The resulting filtrate was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 1.34 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.08 (3H, d, J=6.9 Hz), 526 (1H, q, J=6.9 Hz), 7.05 (1H, d, J=9.1 Hz), 7.15 (2H, d, J=8.6 Hz), 7.53 (2H, d, J=8.7 Hz), 8.49 (1H, dd, J=9.1 Hz, 2.8 Hz), 9.04 (1H, d, J=2.8 Hz).

Reference Example 956 Production of N-[6-(4-chloromethylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide

To a solution of N-(6-(4-hydroxymethylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (3.06 g, 7.9 mmol) in dichloromethane (90 mL) was added thionyl chloride (1.7 mL, 23.3 mmol), and the resulting solution was stirred for 4 hours at room temperature. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was washed with diethyl ether, to thereby yield 2.95 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 4.61 (2H, s), 7.00 (1H, d, J=8.9 Hz), 7.11-7.14 (2H, m), 7.41-7.44 (2H, m), 7.77 (2H, d, J=8.4 Hz), 7.89 (1H, brs), 8.00 (2H, d, J=8.4 Hz), 8.22-8.28 (2H, m).

The following compounds were produced in the same manner as in Reference Example 956.

Reference Example 957 3,4-Dichloro-N-[4-(4-chloromethylphenoxy)-3-fluorophenyl]benzamide

¹H NMR (CDCl₃) δ 4.58 (2H, s), 6.95 (2H, d, J=8.6 Hz), 7.10 (1H, t, J=8.6 Hz), 7.20-7.30 (1H, m), 7.30-7.40 (3H, m), 7.59 (1H, d, J=8.3 Hz), 7.65-7.78 (2H, m), 7.96 (1H, d, J=2.1 Hz).

TABLE 133

Reference Example No. R₄₀₀ R₄₀₁ ¹H NMR (CDCl₃) δ ppm 958 —NO₂ —CH₂Cl 4.63 (2H, s), 7.06 (1H, d, J = 8.9 Hz), 7.16 (2H, dd, J = 6.6 Hz, 2.0 Hz), 7.47 (2H, d, J = 8.3 Hz), 8.47-8.51 (1H, m), 9.04 (1H, d, J = 2.6 Hz) 959 3,4-Cl₂PhCONH— —CH₂Cl 4.59 (2H, s), 6.95 (1H, d, J = 8.9 Hz), 7.10 (2H, d, J = 8.6 Hz), 7.40 (2H, d, J = 8.6 Hz), 7.54 (1H, d, J = 8.2 Hz), 7.71-7.75 (1H, m), 7.99 (1H, d, J = 2.3 Hz), 8.18-8.22 (2H, m), 8.30 (1H, d, J = 2.6 Hz). 960 4-CNPhCONH— —CH₂Cl 4.60 (2H, s), 6.99 (1H, d, J = 8.9 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 8.6 Hz), 7.79 (2H, d, J = 8.3 Hz), 7.97-8.00 (3H, m), 8.21 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.27 (1H, d, J = 2.6 Hz). 961 4-ClPhCONH— —CH₂Cl 4.61 (2H, s), 6.99 (1H, d, J = 9.6 Hz), 7.12 (2H, d, J = 8.3 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.48 (2H, d, J = 8.3 Hz), 7.75 (1H, brs), 7.85 (2H, d, J = 8.3 Hz), 8.20-8.25 (2H, m). 962 —CH₂Cl

2.41-2.45 (4H, m), 3.03 (3H, s), 3.43 (2H, brs), 3.49 (2H, brs), 3.63 (2H, brs), 4.08 (2H, s), 4.54 (2H, s), 5.94 (2H, s), 6.70 (2H, d, J = 9.2 Hz), 6.73-6.77 (2H, m), 6.82 (1H, d, J = 8.6 Hz), 6.85 (1H, brs), 7.00 (2H, d, J = 9.2 Hz), 7.67 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.15 (1H, d, J = 2.5 Hz). (CNPh means a cyanophenyl group. Hereinafter CNPh indicates the same meaning.)

Reference Example 963 Production of 3,4-dichloro-N-{6-[4-(5-chloropentyl)phenoxy]pyridin-3-yl}benzamide hydrochloride

To 3,4-dichloro-N-{6-[4-(5-hydroxypentyl)phenoxy]pyridin-3-yl}benzamide (6.83 g, 15.34 mmol) was added thionyl chloride (35 mL). The resulting solution was stirred for 20 minutes at room temperature, followed by stirring for 1 hour at 50° C. Excess thionyl chloride was evaporated, after which to the resulting residue was added ethyl acetate (100 mL). The obtained white powder was filtered, and washed with ethyl acetate, to thereby yield 6.98 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 1.33-1.50 (2H, m), 1.50-1.68 (2H, m), 1.68-1.85 (2H, m), 2.59 (2H, t, J=7.6 Hz), 3.64 (2H, t, J=6.6 Hz), 7.02 (2H, d, J=8.5 Hz), 7.03 (1H, d, J=9.0 Hz), 7.23 (2H, d, J=8.5 Hz), 7.83 (1H, d, J=8.5 Hz), 7.97 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.20 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.25 (1H, d, J=2.0 Hz), 8.50 (1H, d, J=2.5 Hz), 10.63 (1H, s).

The following compounds were produced in the same manner as in Reference Example 963.

TABLE 134

Refer- ence Exam- ¹H NMR ple (solvent) No. R₄₀₂ R₄₀₃ M Form δ ppm 964 —Cl —Cl 2 free (CDCl₃) 3.04-3.10 (2H, m), 3.69-3.75 (2H, m), 6.95 (1H, d, J = 8.6 Hz), 7.06-7.09 (2H, m), 7.24 (2H, d, J = 8.2 Hz), 7.56 (1H, d, J = 8.2 Hz), 7.69 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.93 (1H, brs), 7.97 (1H, d, J = 2.0 Hz), 8.15-8.19 (1H, m), 8.24 (1H, d, J = 2.6 Hz). 965 —Cl —Cl 3 free (CDCl₃) 2.04-2.12 (2H, m), 2.76-2.81 (2H, m), 3.53-3.58 (2H, m), 6.94 (1H, d, J = 8.9 Hz), 7.04-7.07 (2H, m), 7.20-7.26 (2H, m), 7.56 (1H, d, J = 8.1 Hz), 7.70 (1H, dd, J = 8.4 Hz, 2.2 Hz), 7.90 (1H, brs), 7.97 (1H, d, J = 2.2 Hz), 8.14-8.18 (1H, m), 8.24 (1H, d, J = 2.7 Hz). 966 —CF₃ —H 3 free (CDCl₃) 2.04-2.14 (2H, m), 2.75-2.81 (2H, m), 3.53-3.57 (2H, m), 6.93 (1H, d, J = 8.7 Hz), 7.03-7.07 (2H, m), 7.20-7.23 (2H, m), 7.73 (2H, d, J = 8.2 Hz), 7.97 (2H, d, J = 8.2 Hz), 8.09 (1H, brs), 8.16-8.21 (1H, m), 8.25 (1H, d, J = 2.6 Hz). 967 —Cl —Cl 4 hydro- (DMSO-d₆) 1.60-1.85 (4H, chloride m), 2.62 (2H, t, J = 6.3 Hz), 3.68 (2H, t, J = 6.3 Hz), 7.03 (2H, d, J = 8.5 Hz), 7.04 (1H, d, J = 9.0 Hz), 7.24 (2H, d, J = 8.5 Hz), 7.83 (1H, d, J = 8.6 Hz), 7.97 (1H, dd, J = 8.6 Hz, 2.0 Hz), 8.20 (1H, dd, J = 9.0 Hz, 2.7 Hz), 8.25 (1H, d, J = 2.2 Hz), 8.50 (1H, d, J = 2.7 Hz), 10.64 (1H, s).

Reference Example 968 Production of N-{6-[4-(2-bromoacetyl)phenoxy]pyridin-3-yl}-3,4-dichlorobenzamide

N-[6-(4-acetylphenoxy)pyridin-3-yl}-3,4-dichlorobenzamide (4.0 g, 10 mmol) was dissolved in chloroform (200 mL). To the resulting solution was added copper bromide (5.76 g, 25 mmol), and refluxed overnight. The resulting reaction solution was filtered, and the filtrate was washed with saturated sodium thiosulfate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. To the filtered product from the earlier step was added ethyl acetate, and washed with saturated sodium thiosulfate water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residues were combined for purification by silica gel column chromatography (n-hexane:ethyl acetate 3:1), to thereby yield 1.86 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 4.43 (2H, s), 7.06 (1H, d, J=8.7 Hz), 7.21 (2H, d, J=8.9 Hz), 7.57 (1H, d, J=8.4 Hz), 7.72 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.99 (1H, d, J=2.0 Hz), 8.03 (2H, d, J=8.9 Hz), 8.09 (1H, brs), 8.27 (1H, dd, J=8.7 Hz, 2.8 Hz), 8.32 (1H, d, J=2.2 Hz).

The following compound was produced in the same manner as in Reference Example 968.

Reference Example 969 N-{4-[4-(2-Bromoacetyl)phenoxy]-3-fluorophenyl}-3,4-dichlorobenzamide

¹H NMR (DMSO-D₆) δ 4.88 (2H, s), 7.06 (2H, d, J=8.9 Hz), 7.30-7.50 (1H, m), 7.60-7.70 (1H, m), 7.80-8.20 (5H, m), 8.22 (1H, d, J=2.0 Hz), 10.67 (1H, brs).

Reference Example 970 Production of 4′-[4-(3-bromopropyl)phenoxy]-3,4-dichloro-3′-fluorobenzanilide

To a suspension of 3,4-dichloro-3′-fluoro-4′-[4-(3-hydroxypropyl)phenoxy]benzanilide (2.32 g, 5.34 mmol) in dichloromethane (46 mL) were added carbon tetrabromide (2.13 g, 6.41 mmol) and triphenylphosphine (1.54 g, 5.88 mmol), and the resulting solution was stirred for 12 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate 5:1), to thereby yield 2.41 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.08-2.11 (2H, m), 2.73 (2H, t, J=7.3 Hz), 3.38 (2H, t, J=6.5 Hz), 6.88 (2H, d, J=8.5 Hz), 7.02 (1H, dd, J=9.0 Hz, 8.0 Hz), 7.13 (2H, d, J=8.5 Hz), 7.17-7.28 (1H, m), 7.54 (1H, d, J=8.3 Hz), 7.60-7.74 (2H, m), 7.85 (1H, brs), 7.93 (1H, d, J=2.0 Hz).

The following compounds were produced in the same manner as in Reference Example 97

TABLE 135

Reference Example No. M ¹H NMR (CDCl₃) δ ppm 971 2 3.13 (2H, t, J = 7.5 Hz), 3.55 (2H, t, J = 7.5 Hz), 6.91 (2H, d, J = 6.6 Hz), 7.08 (1H, t, J = 8.7 Hz), 7.15 (2H, d, J = 6.6 Hz), 7.18-7.25 (1H, m), 7.56 (1H, d, J = 8.3 Hz), 7.65-7.75 (2H, m), 7.90-8.00 (2H, m). 972 4 1.67-1.79 (2H, m), 1.81-1.94 (2H, m), 2.60 (2H, t, J = 7.5 Hz), 3.40 (2H, t, J = 6.6 Hz), 6.88 (2H, d, J = 8.6 Hz), 7.02 (1H, dd, J = 9.0 Hz, 8.0 Hz), 7.11 (2H, d, J = 8.6 Hz), 7.14-7.21 (1H, m), 7.55 (1H, d, J = 8.3 Hz), 7.60-7.73 (2H, m), 7.78 (1H, brs), 7.93 (1H, d, J = 1.9 Hz).

Reference Example 973 Production of t-butyl 4-[4-(5-nitropyridin-2-yloxy)benzyl]piperazine-1-carboxylate

To a solution of 2-(4-chloromethylphenoxy)-5-nitropyridine (12.32 g, 47 mmol) in DMF (120 mL) were added triethylamine (19.4 mL, 140 mmol) and t-butyl piperazine-1-carboxylate (11.27 g, 61 mmol), and the resulting solution was stirred for 3 hours at 50° C. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 11.26 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 1.46 (9H, s), 2.40-2.44 (4H, m), 3.43-3.46 (4H, m), 3.54 (2H, s), 7.04 (1H, d, J=8.9 Hz), 7.09-7.14 (2H, m), 7.38-7.44 (2H, m), 8.48 (1H, dd, J=8.9 Hz, 2.8 Hz), 9.05 (1H, d, J=2.8 Hz).

The following compound was produced in the same manner as in Reference Example 973.

Reference Example 974 4-{1-[4-(5-Nitropyridin-2-yloxy)phenyl]ethyl}morpholine

¹H NMR (CDCl₃) δ 1.38 (3H, d, J=6.8 Hz), 2.36-2.54 (4H, m), 3.37 (1H, q, J=6.8 Hz), 3.69-3.72 (4H, m), 7.02 (1H, dd, J=9.1 Hz, 0.5 Hz), 7.11 (2H, d, J=8.6 Hz), 7.40 (2H, d, J=8.5 Hz), 8.47 (1H, dd, J=9.1 Hz, 2.8 Hz), 9.06 (1H, dd, J=2.8 Hz, 0.5 Hz).

Reference Example 975 Production of methanesulfonic acid 6-(4-nitrophenoxy)pyridin-3-ylmethyl ester

[6-(4-nitrophenoxy)pyridin-3-yl]methanol (6.1 g, 24.8 mmol) was dissolved in dichloromethane (150 mL), and to the resulting solution was added, triethylamine (4.15 mL, 29.8 mmol) under ice cooling. To the resulting solution was added dropwise methanesulfonic acid chloride (2.11 mL, 27.3 mmol), and then stirred under a nitrogen atmosphere for 30 minutes at 0° C. The reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. To the residue was added a mixed solvent (50 mL) of n-hexane:ethyl acetate=1:1. The precipitated crystals were removed by suction filtration, to thereby yield 7.9 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 3.04 (3H, s), 5.23 (2H, s), 7.09 (1H, d, J=8.4 Hz), 7.29 (2H, d, J=9.1 Hz), 7.88 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.23 (1H, d, J=2.3 Hz), 8.28 (2H, d, J=9.1 Hz).

The following compounds were produced in the same manner as in Reference Example 975.

TABLE 136

Reference Example No. R₄₀₄ R₄₀₅ ¹H NMR (CDCl₃) δ ppm 976 —CH₃ —NO₂ 2.29 (3H, s), 3.03 (3H, s), 5.22 (2H, s), 7.08 (1H, dd, J = 8.4 Hz, 0.5 Hz), 7.18 (1H, d, J = 8.9 Hz), 7.86 (1H, dd, J = 8.4 Hz, 2.5 Hz), 8.11 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.17 (1H, dd, J = 2.5 Hz, 0.5 Hz), 8.19 (1H, d, J = 2.8 Hz). 977 —H

2.65 (4H, brs), 3.01 (3H, s), 3.65-3.75 (6H, m), 5.22 (2H, s), 5.97 (2H, s), 6.79 (2H, s), 6.92 (1H, s), 7.00 (1H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.6 Hz), 7.47 (2H, d, J = 8.7 Hz), 7.81 (1H, dd, J = 2.5 Hz, 8.4 Hz), 8.20 (1H, d, J = 2.0 Hz).

Reference Example 978 Production of 2-(4-nitrophenoxy)-5-(4-trifluoromethylphenoxymethyl)pyridine

Methanesulfonic acid 6-(4-nitrophenoxy)pyridin-3-ylmethyl ester (4.86 g, 15 mmol) was dissolved in DMF (250 mL), and to the resulting solution were added 4-hydroxybenzotrifluoride (2.92 g, 18 mmol) and potassium carbonate (3.11 g, 22.5 mmol). The resulting solution was stirred under a nitrogen atmosphere for 1 hour at 50° C. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=80:1), to thereby yield 5.8 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 5.09 (2H, s), 7.02-7.10 (3H, m), 7.26-7.31 (2H, m), 7.56-7.59 (2H, m), 7.88 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.25-8.31 (3H, m).

The following compound was produced in the same manner as in Reference Example 978.

Reference Example 979 2-(2-Methyl-4-nitrophenoxy)-5-(4-trifluoromethyl-phenoxymethyl)pyridine

¹H NMR (CDCl₃) δ 2.31 (3H, s), 5.07 (2H, s), 7.03 (2H, d, J=8.6 Hz), 7.08 (1H, d, J=8.4 Hz), 1.17 (1H, d, J=8.9 Hz), 7.57 (2H, d, J=8.4 Hz), 7.87 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.10 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.18 (1H, d, J=2.6 Hz), 8.21 (1H, d, J=2.5 Hz).

Example 1 Production of N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide

To a solution of 4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]benzoic acid (1.19 g, 2.3 mmol) in DMF (30 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (530 mg, 2.8 mmol), 1-hydroxybenzotriazole monohydrate (370 mg, 2.7 mmol) and benzylpiperazine (0.475 mL, 2.7 mmol) under ice cooling. The resulting solution was stirred for 1 day gradually warming up to room temperature. To the residue was added a saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (methanol:chloroform=1:19), to thereby yield 800 mg of the title compound.

Appearance: White needles

¹H NMR (CDCl₃) δ 2.46 (4H, brs), 3.55 (2H, s), 3.72 (4H, brs), 6.96 (1H, d, J=8.9 Hz), 7.10-7.13 (2H, m), 7.28-7.40 (7H, m), 7.74 (2H, d, J=8.3 Hz), 8.02 (2H, d, J=8.3 Hz), 8.16-8.21 (1H, m), 8.32 (1H, d, J=2.6 Hz), 8.53 (1H, brs).

The following compounds were produced in the same manner as in Example 1.

TABLE 137

Example No. R₅₀₁ R₅₀₂ Form mp (° C.) 2 —H —CH₃ hydrochloride 175-176 3 —H benzyl hydrochloride 187-189 4 —H piperonyl free 182-183 5 —H —COOC(CH₃)₃ free 217-220 6 —H —Ac free 152-154 7 —H —(CH₂)₂OH hydrochloride 153-155 8 —F benzyl free 172-173 9 —F piperonyl free 170-171

TABLE 138

Example No. R₅₀₃ R₅₀₄ Form mp (° C.) 10 —H morpholino free 189-192 11 —F morpholino free 203-204 12 —F

free 210-211 13 —F

hydrochloride 233-235 14 —F

hydrochloride 247-249 15 —H

free 174-175 16 —H

hydrochloride 213-216

TABLE 139

Example No. R₅₀₅ R₅₀₆ ¹H NMR (DMSO-d₆) δ ppm 17 —CH₃ —NHAc 1.92 (3H, s), 2.17 (3H, s), 7.13 (1H, d, J = 8.2 Hz), 7.14 (1H, d, J = 8.9 Hz), 7.74 (1H, dd, J = 8.2 Hz, 2.2 Hz), 7.84 (1H, d, J = 8.2 Hz), 7.84 (1H, d, J = 2.2 Hz), 7.95 (1H, dd, J = 8.2 Hz, 2.2 Hz), 8.22 (1H, d, J = 2.2 Hz), 8.23 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.46 (1H, d, J = 2.6 Hz), 9.89 (1H, s), 10.24 (1H, s), 10.57 (1H, s). 18 —H cyclopropyl 0.51-0.60 (2H, m), 0.66-0.74 (2H, m), 2.80-2.89 (1H, m), 7.10-7.20 (3H, m), 7.81-7.89 (3H, m), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.19-8.28 (2H, m), 8.42 (1H, brd), 8.52 (1H, d, J = 2.7 Hz), 10.59 (1H, s). 19 —H cyclohexyl 1.06-1.19 (1H, m), 1.21-1.36 (4H, m), 1.55-1.65 (1H, m), 1.69-1.78 (2H, m), 1.78-1.87 (2H, m), 3.69-3.80 (1H, m), 7.10-7.20 (3H, m), 7.85 (1H, d, J = 8.4 Hz), 7.86-7.92 (2H, m), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.17 (1H, brd), 8.20-8.29 (2H, m), 8.52 (1H, d, J = 2.7 Hz), 10.58 (1H, s). 20 —H cyclopentyl 1.46-1.60 (4H, m), 1.63-1.76 (2H, m), 1.82-1.94 (2H, m), 4.17-4.28 (1H, m), 7.10-7.20 (3H, m), 7.85 (1H, d, J = 8.4 Hz), 7.87-7.92 (2H, m), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.19-8.28 (3H, m), 8.52 (1H, d, J = 2.6 Hz), 10.58 (1H, s). 21 —H cycloheptyl 1.36-1.71 (10H, m), 1.80-1.90 (2H, m), 3.88-4.00 (1H, m), 7.10-7.20 (3H, m), 7.85 (1H, d, J = 8.4 Hz), 7.86-7.92 (2H, m), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.17-8.28 (3H, m), 8.51 (1H, d, J = 2.6 Hz), 10.58 (1H, s). 22 —H cyclododecanyl 1.20-1.57 (20H, m), 1.61-1.73 (2H, m), 4.08-4.21 (1H, m), 7.10-7.21 (3H, m), 7.85 (1H, d, J = 8.4 Hz), 7.88-7.92 (2H, m), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.09 (1H, brd), 8.20-8.29 (2H, m), 8.51 (1H, d, J = 2.7 Hz), 10.58 (1H, s). 23 —H cyclooctyl 1.44-1.65 (8H, m), 1.65-1.80 (6H, m), 3.98-4.09 (1H, m), 7.10-7.20 (3H, m), 7.85 (1H, d, J = 8.4 Hz), 7.88-7.92 (2H, m), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.17-8.27 (3H, m), 8.51 (1H, d, J = 2.7 Hz), 10.58 (1H, s). 24 —H cyclopropyl- 0.19-0.26 (2H, m), 0.38-0.47 (2H, methyl m), 0.99-1.09 (1H, m), 3.12-3.19 (2H, m), 7.12-7.21 (3H, m), 7.85 (1H, d, J = 8.4 Hz), 7.89-7.94 (2H, m), 7.95 (1H, dd, J =8.4 Hz, 2.1 Hz), 8.21-8.29 (2H, m), 8.53 (1H, d, J = 2.8 Hz), 8.54 (1H, brt), 10.60 (1H, s). 25 —H —(CH₂)₂NHAc 1.81 (3H, s), 3.15-3.24 (2H, m), 3.24-3.33 (2H, m), 7.10-7.20 (3H, m), 7.80-8.00 (5H, m), 8.20-8.26 (2H, m), 8.48 (1H, brt), 8.52 (1H, d, J = 2.6 Hz), 10.59 (1H, s).

TABLE 140

Example No. R₅₀₇ Form ¹H NMR (solvent) δ ppm or MS 26 morpholino hydro- ¹H NMR (DMSO-d₆) 3.50-3.65 (8H, m), 7.13-7.19 chloride (3H, m), 7.47 (2H, d, J = 8.6 Hz), 7.84 (1H, d, J = 8.2 Hz), 7.97 (1H, dd, J = 8.3 Hz, 2.0 Hz), 8.23-8.27 (2H, m), 8.54 (1H, d, J = 2.6 Hz), 10.63 (1H, s). 27

free ¹H NMR (CDCl₃) 1.81-1.95 (2H, m), 2.59-2.77 (4H, m), 3.51-3.57 (4H, m), 3.75 (2H, brs), 5.94 (2H, s), 6.71-6.75 (2H, m), 6.83-6.93 (2H, m), 7.05-7.10 (2H, m), 7.32-7.37 (2H, m), 7.54 (1H, d, J = 8.2 Hz), 7.79 (1H, dd, J = 8.3 Hz, 2.0 Hz), 8.06-8.10 (2H, m), 8.30 (1H, s), 8.96 (1H, s). 28

free MS 574 (M⁺) 29

free MS 611 (M⁺) 30 —NH(CH₂)₂OCH₃ free ¹H NMR (DMSO-d₆) 3.32 (3H, s), 3.39-3.48 (4H, m), 7.15-7.20 (3H, m), 7.85 (1H, d, J = 8.3 Hz), 7.86-7.92 (2H, m), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.20-8.26 (2H, m), 8.50 (1H, brt), 8.52 (1H, d, J = 2.5 Hz), 10.59 (1H, s). 31

free MS 601 (M⁺ − 1) 32

free ¹H NMR (DMSO-d₆) 0.86-0.99 (2H, m), 1.10-1.27 (3H, m), 1.50-1.65 (2H, m), 1.65-1.78 (4H, m), 3.06-3.15 (2H, m), 7.11-7.22 (3H, m), 7.85 (1H, d, J = 8.4 Hz), 7.88-7.92 (2H, m), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.20-8.28 (2H, m), 8.40 (1H, brt), 8.52 (1H, d, J = 2.7 Hz), 10.58 (1H, s). 33 —NH(CH₂)₂OPh free ¹H NMR (DMSO-d₆) 3.63 (2H, t, J = 5.8 Hz), 4.12 (2H, t, J = 5.9 Hz), 6.90-7.01 (3H, m), 7.13-7.24 (3H, m), 7.26-7.35 (2H, m), 7.85 (1H, d, J = 8.4 Hz), 7.90-8.00 (3H, m), 8.20-8.30 (2H, m), 8.52 (1H, d, J = 2.6 Hz), 8.69 (1H, brt), 10.59 (1H, s). 34

free MS 574 (M⁺) 35

free ¹H NMR (CDCl₃) 1.80-1.96 (2H, m), 2.61-2.79 (4H, m), 3.45-3.57 (2H, m), 3.62-3.67 (2H, m), 3.75-3.77 (2H, m), 6.94 (1H, d, J = 8.6 Hz), 7.08-7.13 (2H, m), 7.24-7.41 (7H, m), 7.56 (1H, d, J = 8.6 Hz), 7.76 (1H, dd, J = 8.6 Hz, 2.0 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.07-8.14 (1H, m), 8.29 (1H, d, J = 2.0 Hz), 8.39 (1H, s).

TABLE 141

Example No. R₅₀₈ Property 36

mp 221-224° C. 37

mp 228-230° C. 38

mp 193-194° C. 39 —N(CH₃)COOC(CH₃)₃ ¹H NMR (CDCl₃) δ 1.47 (9H, s), 1.45-1.81 (4H, m), 2.73 (3H, s), 2.90 (2H, brs), 4.10 (2H, brs), 4.75 (1H, brs), 6.95 (1H, d, J = 8.7 Hz), 7.11 (2H, d, J = 8.7 Hz), 7.39 (2H, d, J = 8.7 Hz), 7.55 (1H, d, J = 8.2 Hz), 7.77 (1H, dd, J = 8.2 Hz, 2.0 Hz), 8.05 (1H, d, J = 2.0 Hz), 8.14 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.30 (1H, d, J = 2.6 Hz), 8.77 (1H, s). 40 —OPh MS 560 (M⁺ − 1) 41 4-CF₃PhO— MS 629 (M⁺) 42 4-CF₃OPhO— MS 644 (M⁺) 43 4-CNPhO— MS 586 (M⁺) 44 —C₂H₅ MS 496 (M⁺ − 1) 45 —COOC₂H₅ ¹H NMR (CDCl₃) δ 1.27 (3H, t, J = 7.0 Hz), 1.73 (2H, brs), 1.95 (2H, brs), 2.58 (1H, m), 3.08 (2H, brs), 3.86 (1H, brs), 4.16 (2H, q, J = 7.0 Hz), 4.50 (1H, brs), 6.97 (1H, d, J = 9.0 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.40 (2H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.75 (1H, dd, J = 8.5 Hz, 2.0 Hz), 8.03 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 9.0 Hz, 3.0 Hz), 8.30 (1H, d, J = 3.0 Hz), 8.34 (1H, brs). 46 —(CH₂)₂N(CH₃)Ph MS 602 (M⁺) 47 2-FPhCH₂O— MS 592 (M⁺ − 1) 48 PhCH₂O— MS 574 (M⁺ − 1) 49 cyclohexyl MS 550 (M⁺ − 1) 50 4-ClPh— MS 580 (M⁺ + 1) 51 —Ph MS 544 (M⁺ − 1) 52 —CHPh₂ MS 635 (M⁺) 53 2-NH₂PhCO— MS 587 (M⁺ − 1) 54 4-CH₃OPhCONH— MS 617 (M⁺ − 1) 55 —NHCOPh MS 587 (M⁺ − 1) 56 4-CF₃PhCH₂O— mp 186-187° C. 57 4-ClPhCH₂O— mp 176-177° C.

TABLE 142

Example No. R₅₀₉ MS 58

580 (M⁺ − 1) 59

610 (M⁺ − 1) 60

580 (M⁺ − 1) 61

598 (M⁺ − 1) 62

592 (M⁺ − 1) 63 Ph(CH₂)₂N(CH₃)— 600 (M⁺ − 2) 64 Ph₂CH(CH₂)₂N(CH₃)— 691 (M⁺ − 1) 65 4-CH₃SPh(CH₂)₂N(CH₃)— 648 (M⁺) 66

678 (M⁺ + H) 67

613 (M⁺ + H) 68 4-CH₃OPh(CH₂)₄N(CH₃)— 660 (M⁺) 69 4-CH₃Ph(CH₂)₂N(CH₃)— 617 (M⁺ + H) 70 PhO(CH₂)₂N(CH₃)— 618 (M⁺) 71 PhN(CH₃)(CH₂)₂N(CH₃)— 631 (M⁺) 72

608 (M⁺) 73 —O(CH₂)₂Ph 588 (M⁺ − 1) 74

575 (M⁺ − 1) 75

576 (M⁺) 76 4-ClPhCH₂— 594 (M⁺ + 1) 77 4-CF₃PhNH— 644 (M⁺)

TABLE 143

Example No. R₅₁₀ MS  78 4-CH3PhO(CH₂)₂N(CH₃)— 633 (M⁺ + H)  79 Ph(CH₂)₃N(CH₃)— 616 (M⁺)  80 2-phenylmorpholino 630 (M⁺)  81 4-CH₃PhCH₂— 572 (M⁺ − 1)  82 morpholino 554 (M⁺)  83 4-CH₃OPhCH₂O— 606 (M⁺ + H)  84 3-ClPhCH₂O— 608 (M⁺ − 1)  85 2-ClPhCH₂O— 608 (M⁺ − 1)  86 3,4-Cl₂PhCH₂O— 644 (M⁺ + 1)  87 3-CH₃OPhCH₂O— 604 (M⁺ − 1)  88 3,5-(CH₃O)₂PhCH₂O— 634 (M⁺ − 1)  89 4-CH₃PhCH₂O— 588 (M⁺ − 1)  90 3-CH₃PhCH₂O— 588 (M⁺ − 1)  91 2-CH₃PhCH₂O— 588 (M⁺ − 1)  92 3,4-(CH₃)₂PhCH₂O— 602 (M⁺ − 1)  93 4-FPhCH₂O— 592 (M⁺ − 1)  94 3-FPhCH₂O— 592 (M⁺ − 1)  95 3,5-F₂PhCH₂O— 610 (M⁺ − 1)  96 2-CF₃PhCH₂O— 642 (M⁺ − 1)  97 4-CF₃OPhCH₂O— 658 (M⁺ − 1)  98 3-CF₃OPhCH₂O— 658 (M⁺ − 1)  99 2-CF₃OPhCH₂O— 658 (M⁺ − 1) 100

638 (M⁺ − 1)

TABLE 144

Example No. R₅₁₁ mp (° C.) or ¹H NMR (CDCl₃) δ ppm 101

mp 218-220 102

mp 227-231 103

¹H NMR 1.09-1.30 (1H, m), 1.60-1.87 (4H, m), 2.55-2.95 (4H, m), 3.80 (1H, brs), 4.59 (1H, brs), 6.92 (1H, d, J = 8.7 Hz), 7.05-7.35 (9H, m), 7.71 (2H, d, J = 8.6 Hz), 8.04 (2H, d, J = 8.1 Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.34 (1H, d, J = 2.6 Hz), 8.99 (1H, s). 104

¹H NMR 1.27 (3H, t, J = 7.0 Hz), 1.74 (2H, brs), 1.95 (2H, brs), 2.58 (1H, m), 3.08 (2H, brs), 3.92 (1H, brs), 4.17 (2H, q, J = 7.0 Hz), 4.51 (1H, brs), 7.01 (1H, d, J = 9.0 Hz), 7.16 (2H, d, J = 8.5 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.78 (2H, d, J = 8.0 Hz), 7.88 (1H, brs), 8.01 (2H, d, J = 8.0 Hz), 8.24 (1H, dd, J = 9.0 Hz, 3.0 Hz), 8.32 (1H, d, J = 3.0 Hz) 105

¹H NMR 1.46 (9H, s), 1.50-1.90 (4H, m), 2.35-3.00 (2H, m), 2.89 (3H, s), 4.10-4.70 (3H, m), 6.99 (1H, d, J = 8.7 Hz), 7.14 (2H, d, J = 8.3 Hz), 7.40 (2H, d, J = 8.3 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.03 (2H, d, J = 8.1 Hz), 8.22 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.33 (1H, d, J = 2.6 Hz), 8.34 (1H, brs).

TABLE 145

Example ¹H NMR (CDCl₃) δ ppm No. R₅₁₂ or MS 106 4-CH₃OPhCH(Ph)— MS 665 (M⁺ − 1) 107 4-CH₃OPhCOCH₂— ¹H NMR 2.63 (4H, brs), 3.65 (4H, brs), 3.82 (2H, s), 3.88 (3H, s), 6.92-6.98 (3H, m), 7.12 (2H, d, J = 8.7 Hz), 7.41 (2H, d, J = 8.7 Hz), 7.56 (1H, d, J = 8.2 Hz), 7.75 (1H, dd, J = 8.2 Hz, 2.1 Hz), 7.97 (2H, d, J = 8.9 Hz), 8.03 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.30 (1H, d, J = 2.8 Hz), 8.39 (1H, s). 108 4-ClPhCOCH₂— ¹H NMR 2.63 (4H, brs), 3.66 (4H, brs), 3.83 (2H, s), 6.97 (1H, d, J = 8.7 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.39-7.47 (4H, m), 7.56 (1H, d, J = 8.4 Hz), 7.74 (1H, dd, J = 8.2 Hz, 2.1 Hz), 7.94 (2H, d, J = 8.6 Hz), 8.02 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.30 (1H, d, J = 2.8 Hz), 8.37 (1H s). 109 3-pyridyl ¹H NMR 3.20 (4H, brs), 3.78 (4H, brs), 6.93 (1H, d, J = 8.7 Hz), 7.11 (2H, d, J = 8.6 Hz), 7.19-7.21 (2H, m), 7.39 (2H, d, J = 8.6 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.03 (1H, d, J = 2.0 Hz), 8.11-8.25 (3H, m), 8.36 (1H, d, J = 2.5 Hz), 9.81 (1H, s). 110 —CH₂CONHPh MS 603 (M⁺) 111 2-pyridyl MS 547 (M⁺) 112 4-pyridyl MS 547 (M⁺) 113

MS 548 (M⁺) 114

MS 548 (M⁺) 115 —(CH₂)₄Ph MS 603 (M⁺ + H) 116 —CH(C₂H₅)₂ MS 540 (M⁺) 117 —CH(CH₃)₂ MS 511 (M⁺ − 1) 118 —(CH₂)₂N(CH₃)₂ MS 540 (M⁺ − 1)

TABLE 146

Example No. R₅₁₃ R₅₁₄ R₅₁₅ R₅₁₆ MS (M⁺) 119 —F —H —H —H 564 120 —Cl —H —H —H 582 121 —CF₃ —H —H —H 614 122 —OCH₃ —H —H —H 576 123 —CH₃ —H —H —H 560 124 —H —CF₃ —H —H 614 125 —H —Cl —H —H 582 126 —H —OCH₃ —H —H 576 127 —H —CH₃ —H —H 560 128 —H —H —CN —H 571 129 —H —H —OCF₃ —H 630 130 —H —H —CO₂C(CH₃)₃ —H 646 131 —H —H —F —H 564 132 —H —H —Cl —H 580 133 —H —H —OCH₃ —H 576 134 —H —H —CH₃ —H 560 135 —H —H —CF₃ —H 614 136 —H —H —Ph —H 622 137 —Cl —Cl —H —H 616 138 —CH₃ —CH₃ —H —H 574 139 —H —CH₃ —CH₃ —H 574 140 —F —H —F —H 582 141 —OCH₃ —H —H —Cl 612

TABLE 147

Example No. R₅₁₇ R₅₁₈ R₅₁₉ mp (° C.) or ¹H NMR (CDCl₃) δppm 142 —H —H —H ¹H NMR 3.20(4H, brs), 3.79(4H, brs), 6.89-6.96(3H, m), 7.00(1H, d, J = 8.9 Hz), 7.14-7.19(2H, m), 7.27-7.33(2H, m), 7.43-7.48(2H, m), 7.76(2H, d, J = 8.1 Hz), 8.02(2H, d, J = 8.1 Hz), 8.23(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.31-8.34(2H, m). 143 —F —H —H mp 193-194 144 —Cl —H —H ¹H NMR 3.07(4H, brs), 3.82(4H, brs), 7.00-7.06(3H, m), 7.18(2H, d, J = 8.4 Hz), 7.22-7.26(1H, m), 7.38-7.41(1H, m), 7.48(2H, d, J = 8.6 Hz), 7.77(2H, d, J = 8.1 Hz), 8.04(2H, d, J = 8.1 Hz), 8.24(1H, dd, J = 8.9 Hz, 2.4 Hz), 8.30(1H, brs), 8.35(1H, d, J = 2.4 Hz). 145 —H —Cl —H ¹H NMR 3.19(4H, brs), 3.76(4H, brs), 6.77-6.81(1H, m), 6.86-6.88 (2H, m), 6.99(1H, d, J = 8.9 Hz), 7.13-7.22(3H, m), 7.40-7.45(2H, m), 7.73(2H, d, J = 8.4 Hz), 8.02(2H, d, J = 8.4 Hz), 8.21(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.34(1H, d, J = 2.7 Hz), 8.56(1H, s). 146 —H —CH₃ —H ¹H NMR 2.31(3H, s), 3.15(4H, brs), 3.74(4H, brs), 6.71-6.73(3H, m), 6.97(1H, d, J = 8.9 Hz), 7.11-7.18(3H, m), 7.42(2H, d, J = 8.1 Hz), 7.72(2H, d, J = 8.1 Hz), 8.01(2H, d, J = 8.1 Hz), 8.18-8.21(1H, m), 8.34(1H, brs), 8.54(1H, brs). 147 —H —OCH₃ —H ¹H NMR 3.07(4H, brs), 3.73(4H, brs), 3.88(3H, s), 6.88-7.08(5H, m), 7.13-7.17(2H, m), 7.42-7.47(2H, m), 7.75(2H, d, J = 8.4 Hz), 8.03 (2H, d, J = 7.8 Hz), 8.21(1H, dd, J = 8.9 Hz, 2.4 Hz), 8.34(1H, d, J = 2.4 Hz), 8.45(1H, brs). 148 —H —CF₃ —H mp 147-177 149 —H —H —OH mp 241-242 150 —H —H —OCH₃ ¹H NMR 3.06(4H, brs), 3.63-3.91(7H, m), 6.83-6.93(4H, m), 6.99(1H, d, J = 8.6 Hz), 7.15(2H, d, J = 8.4 Hz), 7.44(2H, d, J = 8.4 Hz), 7.75 (2H, d, J = 8.4 Hz), 8.02(2H, d, J = 8.1 Hz), 8.22(1H, dd, J = 8.9 Hz, 2.4 Hz), 8.33(1H, d, J = 2.4 Hz), 8.40(1H, brs). 151 —H —H —CN ¹H NMR 3.23(4H, brs), 3.79(4H, brs), 7.01(1H, d, J = 8.9 Hz), 7.12-7.19(5H, m), 7.33- 7.39(1H, m), 7.43-7.48(2H, m), 7.74(2H, d, J = 8.4 Hz), 8.02(2H, d, J = 8.4 Hz), 8.23(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.35(1H, d, J = 2.7 Hz), 8.47(1H, s).

TABLE 148

Example No. R₅₂₀ R₅₂₁ ¹H NMR (solvent) δppm or MS 152 —H piperonyl ¹H NMR (CDCl₃) 2.38-2.45(4H, m), 3.45(2H, s), 3.49-3.74 (4H, m), 5.95(2H, s), 6.74(2H, s), 6.85(1H, s), 6.97(1H, d, J = 8.6 Hz), 7.10(2H, d, J = 8.9 Hz), 7.41(2H, d, J = 8.9 Hz), 7.58(1H, d, J = 8.3 Hz), 7.74(1H, dd, J = 8.3 Hz, 2.0 Hz), 8.02 (1H, d, J = 2.3 Hz), 8.13-8.20(2H, m), 8.29(1H, d, J = 2.6 Hz). 153 —H —COOC(CH₃)₃ ¹H NMR (DMSO-d₆) 1.41(9H, s), 3.39-3.50(8H, m), 7.13-7.19(3H, m), 7.45- 7.48(2H, m), 7.84(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21- 8.26(2H, m), 8.52(1H, d, J = 2.3 Hz), 10.58(1H, s). 154 —H 2-naphthylmethyl MS 611(M⁺ + 1) 155 —H

MS 671(M⁺ + 1) 156 —H 1-naphthylmethyl MS 611 (M⁺ + H) 157 —CH₃ 3,4-(CH₃O)₂PhCH₂— MS 633(M⁺ + 1) 158 —H

MS 631(M⁺ ⁻1) 159 —H —CH(CH₃)Ph MS 573(M⁺ ⁻1) 160 —H

MS 637(M⁺) 161 —H (4-FPh)₂CH— MS 671(M⁺ ⁻1) 162 —H —(CH₂)₃CH₃ MS 526(M⁺) 163 —H —(CH₂)₃Ph MS 588(M⁺) 164 —H cyclopentyl MS 538(M⁺) 165 —H cycloheptyl MS 565(M⁺ ⁻1)

TABLE 149

Example No. R₅₂₂ MS 166

567(M⁺) 167

581(M⁺) 168

583(M⁺) 169

567(M⁺) 170 4-pyridylmethyl 561(M⁺) 171 2-pyridylmethyl 562(M⁺ + H) 172

643(M⁺ + H) 173

580(M⁺) 174

643(M⁺)

TABLE 150

Example No. R₅₂₃ R₅₂₄ mp (° C.) or ¹H NMR (solvent) δppm 175 —H 3-pyridyl ¹H NMR (CDCl₃) 3.21(4H, brs), 3.78(4H, brs), 6.98(1H, d, J = 8.7 Hz), 7.13-7.21(4H, m), 7.41-7.44(2H, m), 7.70(2H, d, J = 8.1 Hz), 8.02(2H, d, J = 8.1 Hz), 8.12-8.14(1H, m), 8.20-8.27 (2H, m), 8.35(1H, d, J = 2.6 Hz), 8.99(1H, s). 176 —H 2-pyridyl mp 222-224 177 —F 3-pyridyl ¹H NMR (CDCl₃) 3.21(4H, brs), 3.79(4H, brs), 7.05(1H, d, J = 8.4 Hz), 7.20-7.30(5H, m), 7.71(2H, d, J = 8.2 Hz), 8.00(2H, d, J = 8.2 Hz), 8.14(1H, brs), 8.21-8.25(3H, m), 8.78(1H, s). 178 —H

mp 205-206 179 —H

¹H NMR (DMSO-d₆) 2.38(4H, brs), 2.43(2H, t, J = 7.5 Hz), 2.86(2H, t, J = 7.5 Hz), 3.41(2H, s), 3.45(4H, brs), 6.80(1H, d, J = 7.9 Hz), 7.06(1H, d, J = 7.9 Hz), 7.10(1H, s), 7.15(1H, d, J = 8.8 Hz), 7.17(2H, d, J = 8.4 Hz), 7.44(2H, d, J = 8.4 Hz), 7.94(2H, d, J = 8.0 Hz), 8.17(2H, d, J = 8.0 Hz), 8.26(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.54(1H, d, J = 2.6 Hz), 10.06( 1H, s), 10.68(1H, s). 180 —H

¹H NMR (CDCl₃) 1.71-2.05(4H, m), 2.58(4H, brs), 3.16(2H, s), 3.36- 3.53(4H, m), 3.55(2H, brs), 3.74(2H, brs), 7.00(1H, d, J = 8.9 Hz), 7.14(2H, d, J = 8.6 Hz), 7.42(2H, d, J = 8.6 Hz), 7.76(2H, d, J = 8.1 Hz), 8.04(2H, d, J = 8.1 Hz), 8.26(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.34(1H, d, J = 2.6 Hz), 8.50(1H, s). 181 —H —COOC(CH₃)₃ ¹H NMR (CDCl₃) 1.48(9H, s), 3.45(4H, brs), 3.58(4H, brs), 6.99(1H, d, J = 8.7 Hz), 7.15(2H, d, J = 8.7 Hz), 7.41(2H, d, J = 8.7 Hz), 7.74(2H, d, J = 8.2 Hz), 8.02(2H, d, J = 8.2 Hz), 8.21(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.33(1H, d, J = 2.6 Hz), 8.43 (1H, brs). 182 —H —CH₂COOC₂H₅ ¹H NMR (CDCl₃) 1.28(3H, t, J = 7.1 Hz), 2.61(4H, brs), 3.26 (2H, s), 3.57(2H, brs), 3.78(2H, brs), 4.19(2H, q, J = 7.1 Hz), 6.97(1H, d, J = 8.7 Hz), 7.12(2H, d, J = 8.7 Hz), 7.40(2H, d, J = 8.7 Hz), 7.74(2H, d, J = 8.1 Hz), 8.03(2H, d, J = 8.1 Hz), 8.19(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.33(1H, d, J = 2.6 Hz), 8.61 (1H, brs). 183 —H —CH₂CONHNHCOOC(CH₃)₃ ¹H NMR (CDCl₃) 1.46(9H, s), 2.60(4H, brs), 3.17(2H, s), 3.67 (4H, brs), 6.48(1H, brs), 7.00(1H, d, J = 8.7 Hz), 7.14(2H, d, J = 8.5 Hz), 7.41(2H, d, J = 8.5 Hz), 7.75(2H, d, J = 8.1 Hz), 8.02(2H, d, J = 8.1 Hz), 8.24(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.33 (1H, d, J = 2.6 Hz), 8.53(2H, s).

TABLE 151

Example mp (° C.) or ¹H NMR No. R₅₂₅ R₅₂₆ R₅₂₇ R₅₂₈ R₅₂₉ Form (solvent) δppm 184 —Cl —Cl —H —F 3-pyridyl free ¹H NMR (CDCl₃) 3.21(4H, brs), 3.79 (4H, brs), 7.02(1H, d, J = 8.7 Hz), 7.18-7.28(5H, m), 7.49(1H, d, J = 8.2 Hz), 7.74(1H, dd, J = 8.2 Hz, 1.7 Hz), 8.00(1H, d, J = 1.7 Hz), 8.13(1H, brs), 8.17-8.21(1H, m), 8.26(2H, d, J = 2.3 Hz), 9.33(1H, brs). 185 —H —Cl —H —H 4-CNPhCH₂— free mp 199-201 186 —OCF₃ —H —H —H 3-pyridylmethyl free ¹H NMR (CDCl₃) 2.43-2.55(4H, m), 3.43-3.71(6H, m), 6.90(1H, d, J = 8.7 Hz), 7.05-7.08(2H, m), 7.25-7.46(5H, m), 7.66-7.69(1H, m), 7.82-7.88(2H, m), 8.15(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.36(1H, d, J = 2.5 Hz), 8.48(1H, dd, J = 4.8 Hz, 1.7 Hz), 8.51(1H, d, J = 1.7 Hz), 9.84(1H, s). 187 —CF₃ —H —H —H 4-CNPhCH₂— free mp 193-197 188 —F —H —CF₃ —H 4-CNPhCH₂— oxalate mp 136-139 189 —CH₃ —CH₃ —H —H —COOC(CH₃)₃ free ¹H NMR (CDCl₃) 1.48(9H, s), 2.34 (6H, s), 3.46(4H, brs), 3.60(4H, brs), 6.99(1H, d, J = 8.7 Hz), 7.14-7.17 (2H, m), 7.23-7.26(1H, m), 7.42-7.47 (2H, m), 7.61(1H, dd, J = 7.8 Hz, 2.0 Hz), 7.67(1H, d, J = 2.0 Hz), 7.93(1H, brs), 8.25- 8.31(2H, m).

TABLE 152

Example No. R₅₃₀ R₅₃₁ R₅₃₂ R₅₃₃ R₅₃₄ MS 190 —Cl —H —H —H —H 594(M⁺) 191 —OCH₃ —H —H —H —H 590(M⁺) 192 —CH₃ —H —H —H —H 574(M⁺) 193 —F —H —H —H —H 578(M⁺) 194 —NO₂ —H —H —H —H 603(M⁺ ⁻2) 195 —CF₃ —H —H —H —H 628(M⁺) 196 —OCF₃ —H —H —H —H 645(M⁺ + 1) 197 —H —Cl —H —H —H 595(M⁺ + 1) 198 —H —F —H —H —H 579(M⁺ + 1) 199 —H —NO₂ —H —H —H 605(M⁺) 200 —H —CF3 —H —H —H 628(M⁺) 201 —H —OCF₃ —H —H —H 644(M⁺) 202 —H —COOCH₃ —H —H —H 618(M⁺) 203 —H —H —Cl —H —H 594(M⁺) 204 —H —H —F —H —H 578(M⁺) 205 —H —H —NO₂ —H —H 605(M⁺) 206 —H —H —COOCH₃ —H —H 618(M⁺) 207 —H —H —Ph —H —H 636(M⁺) 208 —H —H —C₂H₅ —H —H 588(M⁺) 209 —Cl —Cl —H —H —H 630(M⁺) 210 —Cl —H —Cl —H —H 630(M⁺) 211 —H —F —H —F —H 596(M⁺) 212 —H —OCH₃ —H —OCH₃ —H 622(M⁺ + 2) 213 —F —H —F —H —H 596(M⁺) 214 —H —Cl —Cl —H —H 630(M⁺) 215 —F —H —H —H —F 596(M⁺) 216 —Cl —H —H —H —Cl 630(M⁺) 217 —F —H —H —F —H 596(M⁺) 218 —Cl —H —H —Cl —H 629(M⁺ + 1) 219 —H —Cl —OCH₃ —H —H 624(M⁺)

TABLE 153

Example No. R₅₃₅ R₅₃₆ R₅₃₇ R₅₃₈ mp (° C.) or ¹H NMR (CDCl₃) δppm 220 —Cl —Cl —H —H mp 164-166 221 —Cl —Cl —F —H ¹H NMR 2.46(4H, brs), 3.39-3.82(6H, m), 7.00(1H, d, J = 8.9 Hz), 7.13-7.33(8H, m), 7.52(1H, d, J = 8.4 Hz), 7.72(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.00(1H, d, J = 2.0 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.23(1H, d, J = 2.6 Hz), 8.61(1H, brs). 222 —CF₃ —H —F —H ¹H NMR 2.44(4H, brs), 3.42-3.78(6H, m), 6.97(1H, d, J = 8.7 Hz), 7.09-7.36(8H, m), 7.66(2H, d, J = 8.1 Hz), 7.96(2H, d, J = 8.1 Hz), 8.16(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.26(1H, d, J = 2.5 Hz), 9.04(1H, brs). 223 —Cl —Cl —Cl —H ¹H NMR 2.47(4H, brs), 3.42-3.83(6H, m), 7.00(1H, d, J = 8.9 Hz), 7.17(1H, d, J = 8.2 Hz), 7.25- 7.33(6H, m), 7.46(1H, d, J = 1.8 Hz), 7.53(1H, d, J = 8.4 Hz), 7.74(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.01(1H, d, J = 2.1 Hz), 8.17(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.6 Hz), 8.64(1H, brs). 224 —CF₃ —H —Cl —H ¹H NMR 2.47(4H, brs), 3.42-3.82(6H, m), 7.02(1H, d, J = 8.9 Hz), 7.19(1H, d, J = 8.4 Hz), 7.27- 7.33(6H, m), 7.47(1H, d, J = 1.8 Hz), 7.73(2H, d, J = 8.4 Hz), 8.00(2H, d, J = 7.9 Hz), 8.20-8.26(2H, m), 8.46(1H, brs). 225 —Cl —Cl —CH₃ —H ¹H NMR 2.15(3H, s), 2.45(4H, brs), 3.46-3.75(6H, m), 6.85 (1H, d, J = 8.9 Hz), 6.95(1H, d, J = 8.4 Hz), 7.13-7.33(7H, m), 7.50(1H, d, J = 8.6 Hz), 7.75(1H, dd, J = 8.4 Hz, 2.2 Hz), 8.03 (1H, d, J = 2.2 Hz), 8.08(1H, dd, J = 8.9 Hz, 3.0 Hz), 8.27(1H, d, J = 3.0 Hz), 9.06(1H, s). 226 —CF₃ —H —CH₃ —H ¹H NMR 2.17(3H, s), 2.44(4H, brs), 3.40-3.82(6H, m), 6.88 (1H, d, J = 8.9 Hz), 6.98(1H, d, J = 8.1 Hz), 7.14-7.18(1H, m), 7.23-7.33(6H, m), 7.70(2H, d, J = 8.4 Hz), 8.01(2H, d, J = 8.1 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.30(1H, d, J = 2.7 Hz), 8.90(1H, brs). 227 —Cl —Cl —OCH₃ —H mp 197-199 228 —CF₃ —H —OCH₃ —H mp 152-154 229 —Cl —Cl —H —CH₃ mp 182-183 230 —CF₃ —H —H —CH₃ mp 188-190 231 —Cl —Cl —H —OCH₃ mp 196-198 232 —CF₃ —H —H —OCH₃ ¹H NMR 2.32-2.50(4H, m), 3.30(2H, brs), 3.53(2H, s), 3.70-3.81(5H, m), 6.61-6.65(2H, m), 6.91(1H, d, J = 8.9 Hz), 7.11-7.15(1H, m), 7.26-7.36(5H, m), 7.72(2H, d, J = 8.4 Hz), 8.05-8.13(3H, m), 8.36(1H, d, J = 2.4 Hz). 9.07(1H, s).

TABLE 154

Example No. R₅₃₉ R₅₄₀ R₅₄₁ R₅₄₂ Form mp (° C.) or ¹H NMR (solvent) δppm 233 —CF₃ —H —H —H hydrochloride ¹H NMR (DMSO-d₆) 2.90-3.70(6H, m), 3.80-4.60(2H, m), 4.24(2H, brs), 6.07(2H, s), 6.98(1H, d, J = 8.0 Hz), 7.05(1H, dd, J = 8.0 Hz, 1.5 Hz), 7.16(1H, d, J = 8.7 Hz), 7.20(2H, d, J = 8.6 Hz), 7.27(1H, s), 7.52(2H, d, J = 8.6 Hz), 7.93(2H, d, J = 8.3 Hz), 8.21(2H, d, J = 8.3 Hz), 8.30(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.60(1H, d, J = 2.6 Hz), 10.80(1H, s). 234 —Cl —Cl —F —H free ¹H NMR (CDCl₃) 2.42(4H, brs), 3.37-3.79(6H, m), 5.94(2H, s), 6.70-6.77(2H, m), 6.84(1H, brs), 6.96(1H, d, J = 8.7 Hz), 7.10-7.22(3H, m), 7.47(1H, d, J = 8.2 Hz), 7.72(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.99(1H, d, J = 2.0 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.6 Hz), 9.14(1H, brs). 235 —CF₃ —H —F —H free ¹H NMR (CDCl₃) 2.41(4H, brs), 3.37-3.79(6H, m), 5.94(2H, s), 6.69-6.76(2H, m), 6.84(1H, s), 6.99(1H, d, J = 8.9 Hz), 7.10-7.26(3H, m), 7.67(2H, d, J = 8.1 Hz), 7.97(2H, d, J = 8.1 Hz), 8.17(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.26(1H, d, J = 2.5 Hz), 8.89(1H, brs). 236 —Cl —Cl —Cl —H free ¹H NMR (CDCl₃) 2.45(4H, brs), 3.38-3.81(6H, m), 5.95(2H, s), 6.71-6.78(2H, m), 6.85(1H, s), 7.01(1H, d, J = 8.7 Hz), 7.17-7.30(2H, m), 7.45-7.47(1H, m), 7.54(1H, d, J = 8.4 Hz), 7.70-7.74(1H, m), 8.00(1H, d, J = 1.8 Hz), 8.17(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz), 8.48(1H, s). 237 —CF₃ —H —CH₃ —H free ¹H NMR (CDCl₃) 2.45(4H, brs), 3.40-3.81(6H, m), 5.95(2H, s), 6.71-6.77(2H, m), 6.85(1H, s), 7.03(1H, d, J = 8.6 Hz), 7.20(1H, d, J = 8.2 Hz), 7.28-7.31(1H, m), 7.48(1H, d, J = 2.0 Hz), 7.74(2H, d, J = 8.4 Hz), 8.00(2H, d, J = 8.2 Hz), 8.21- 8.26(2H, m), 8.34(1H, brs). 238 —CF₃ —H —CH₃ —H free ¹H NMR (CDCl₃) 2.16(3H, s), 2.42(4H, brs), 3.44-3.70(6H, m), 5.94(2H, s), 6.70-6.77(2H, m), 6.85-6.89(2H, m), 6.97(1H, d, J = 8.4 Hz), 7.14-7.23(2H, m), 7.69(2H, d, J = 8.1 Hz), 8.01(2H, d, J = 8.1 Hz), 8.13-8.17(1H, m), 8.30(1H, d, J = 2.7 Hz), 8.97(1H, brs). 239 —Cl —Cl —OCH₃ —H free mp 194-196 240 —CF₃ —H —OCH₃ —H free mp 134-136 241 —CF₃ —H —H —CH₃ free mp 199-201 242 —CF₃ —H —H —OCH free mp 192-193

TABLE 155

Example No. R₅₄₃ R₅₄₄ R₅₄₅ ¹H NMR (CDCl₃) δppm 243 —Cl —Cl benzyl 2.39-2.62(4H, m), 3.42-3.91(6H, m), 6.94(1H, d, J = 8.9 Hz), 7.28-7.33(6H, m), 7.41(1H, dd, J = 8.4 Hz, 1.6 Hz), 7.50-7.53 (2H, m), 7.72-7.75(2H, m), 7.81-7.84(2H, m), 8.02(1H, d, J = 2.1 Hz), 8.14(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.28(1H, d, J = 2.7 Hz), 8.66(1H, s). 244 —Cl —Cl piperonyl 2.41-2.74(4H, m), 3.42-3.91(6H, m), 5.94(2H, s), 6.73(2H, brs), 6.84(1H, brs), 6.97(1H, d, J = 8.9 Hz), 7.29-7.33(1H, m), 7.42 (1H, d, J = 8.2 Hz), 7.52-7.57(2H, m), 7.71-7.85(4H, m), 8.02 (1H, d, J = 2.0 Hz), 8.18(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.28(1H, d, J = 2.8 Hz), 8.48(1H, brs). 245 —Cl —Cl 3-pyridyl 3.25(4H, brs), 3.82(4H, brs), 7.01(1H, d, J = 8.7 Hz), 7.21-7.22 (2H, m), 7.35(1H, dd, J = 8.9 Hz, 2.3 Hz), 7.47-7.50(1H, m), 7.52-7.56(2H, m), 7.74(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.80(1H, d, J = 8.6 Hz), 7.86-7.91(2H, m), 8.01(1H, d, J = 2.0 Hz), 8.13-8.15(1H, m), 8.18-8.22(1H, m), 8.29-8.31(2H, m), 8.42 (1H, brs). 246 —CF₃ —H benzyl 2.35-2.58(4H, m), 3.37-3.87(6H, m), 6.96(1H, d, J = 8.9 Hz), 7.28-7.34(6H, m), 7.41(1H, dd, J = 8.4 Hz, 1.5 Hz), 7.52(1H, d, J = 2.0 Hz), 7.64-7.76(3H, m), 7.83(2H, d, J = 9.1 Hz), 8.00(2H, d, J = 8.2 Hz), 8.19(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.30(1H, d, J = 2.6 Hz), 8.68(1H, brs). 247 —CF₃ —H piperonyl 2.30-2.58(4H, m), 3.35-3.87(6H, m), 5.94(2H, s), 6.70-6.77 (2H, m), 6.85(1H, brs), 6.95(1H, d, J = 8.7 Hz), 7.31(1H, dd, J = 8.9 Hz, 2.1 Hz), 7.39(1H, d, J = 8.4 Hz), 7.51(1H, brs), 7.66- 7.83(5H, m), 7.99(2H, d, J = 8.1 Hz), 8.17(1H, dd, J = 8.7 Hz, 2.3 Hz), 8.30(1H, brs), 8.89(1H, brs). 248 —CF₃ —H 3-pyridyl 3.22(4H, brs), 3.79(4H, brs), 6.99(1H, d, J = 8.7 Hz), 7.17-7.23 (2H, m), 7.33(1H, dd, J = 8.9 Hz, 2.3 Hz), 7.45(1H, dd, J = 8.4 Hz, 1.5 Hz), 7.54(1H, d, J = 2.3 Hz), 7.66(2H, d, J = 8.4 Hz), 7.76-7.86(3H, m), 7.99(2H, d, J = 8.1 Hz), 8.13(1H, brs), 8.21-8.25(1H, m), 8.28(1H, brs), 8.33(1H, d, J = 2.5 Hz), 9.13(1H, s).

TABLE 156

Example No. R₅₄₆ R₅₄₇ R₅₄₈ ¹H NMR (CDCl₃) δppm 249 —Cl —Cl benzyl 2.27-2.34(2H, m), 2.58-2.61(2H, m), 3.20- 3.29(2H, m), 3.53 (2H, s), 3.90-3.99(2H, m), 6.91(1H, d, J = 8.7 Hz), 7.29-7.32 (7H, m), 7.39- 7.45(1H, m), 7.53-7.56(2H, m), 7.71-7.81(3H, m), 8.00-8.04(2H, m), 8.25(1H, d, J = 2.6 Hz), 8.47(1H, s). 250 —Cl —Cl piperonyl 2.25-2.31(2H, m), 2.55-2.59(2H, m), 3.22(2H, brs), 3.44(2H, s), 3.86-4.01(2H, m), 5.94(2H, s), 6.69- 6.76(2H, m), 6.84-6.91 (2H, m), 7.25- 7.29(2H, m), 7.38-7.44(1H, m), 7.52-7.55(2H, m), 7.71-7.80(3H, m), 7.97-8.03(2H, m), 8.24(1H, d, J = 2.8 Hz), 8.60(1H, s). 251 —CF₃ —H benzyl 2.27-2.34(2H, m), 2.57-2.61(2H, m), 3.23- 3.25(2H, m), 3.53 (2H, s), 3.89-3.98(2H, m), 6.96(1H, d, J = 8.7 Hz), 7.27-7.31 (7H, m), 7.40- 7.45(1H, m), 7.55(1H, d, J = 2.3 Hz), 7.72-7.83 (4H, m), 8.00(2H, d, J = 8.1 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.30(1H, d, J = 2.6 Hz), 8.40(1H, brs). 252 —CF₃ —H piperonyl 2.25-2.31(2H, m), 2.55-2.58(2H, m), 3.23(2H, m), 3.43(2H, s), 3.85-4.00(2H, m), 5.94(2H, s), 6.70-6.76(2H, m), 6.84(1H, s), 6.96(1H, d, J = 8.9 Hz), 7.28-7.31(2H, m), 7.40-7.46(1H, m), 7.55(1H, d, J = 2.5 Hz), 7.72-7.83(4H, m). 8.00(2H, d, J = 7.9 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.30(1H, d, J = 2.6 Hz), 8.44(1H, brs).

TABLE 157

Example No. R₅₄₉ R₅₅₀ R₅₅₁ R₅₅₂ R₅₅₃ Form ¹H NMR (solvent) δppm 253 —CF₃ —H —CH₃ —H 3-pyridyl free (CDCl₃) 3.06(3H, s), 3.22(4H, brs), 3.81(4H, brs), 4.55(2H, s), 6.87(1H, d, J = 8.9 Hz), 7.09 (2H, d, J = 8.7 Hz), 7.14(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.19- 7.21(2H, m), 7.35(2H, d, J = 7.9 Hz), 7.44(2H, d, J = 8.7 Hz), 7.60(2H, d, J = 8.1Hz), 7.74(1H, d, J = 3.0 Hz), 8.14-8.17(1H, m), 8.31-8.33(1H, m). 254 —CF₃ —H —H —F benzyl free (CDCl₃) 2.46(4H, brs), 3.54(6H, brs), 4.11(1H, brs), 4.38(2H, brs), 6.85(1H, d, J = 8.7 Hz), 7.01(1H, dd, J = 8.7 Hz, 3.1 Hz), 7.16-7.25(3H, m), 7.28- 7.33(5H, m), 7.46(2H, d, J = 8.1 Hz), 7.52(1H, d, J = 2.6 Hz), 7.60(2H, d, J = 8.1Hz). 255 —CF₃ —H —CH₃ —H piperonyl hydrochloride (DMSO-d₆) 2.49-2.52(2H, m), 3.06(5H, brs), 3.35(4H, brs), 4.22(2H, brs), 4.68(2H, brs), 6.07(2H, s), 6.94- 7.05(5H, m), 7.23(1H, brs), 7.32(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.43-7.46(4H, m), 7.69-7.72(3H, m), 11.23(1H, brs). 256 —Cl —Cl —H —F benzyl free (CDCl₃) 2.47(4H, brs), 3.49-3.68(6H, m), 4.29 (2H, s), 6.86(1H, d, J = 8.7 Hz), 7.01(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.17-7.22(4H, m), 7.32(5H, brs), 7.41(1H, d, J = 8.3 Hz), 7.45(1H, d, J = 1.8 Hz), 7.51(1H, d, J = 3.0 Hz). 257 —CF₃ —H —CH₃ —H 4-CH₃OPhCH₂— hydrochloride (DMSO-d₆) 2.49-2.52(2H, m), 3.06(5H, brs), 3.32- 3.38(4H, m), 3.78(3H, s), 4.27(2H, d, J = 4.1 Hz), 4.68(2H, brs), 6.96(1H, d, J = 8.9 Hz), 7.00-7.05(4H, m), 7.32(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.43-7.49(6H, m), 7.68-7.72(3H, m), 10.72(1H, brs). 258 —CF₃ —H —CH₃ —H 4-pyridylmethyl hydrochloride (DMSO-d₆) 2.49-2.52(2H, m), 3.05-3.44(9H, m), 4.26(2H, brs), 4.68(2H, brs), 6.96(1H, d, J = 8.9 Hz), 7.03(2H, d, J = 8.7 Hz), 7.32(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.42-7.47(4H, m), 7.68-7.72(5H, m), 8.71(2H, dd, J = 4.6 Hz, 1.5 Hz).

TABLE 158

Example No. R₅₅₄ R₅₅₅ R₅₅₆ Form ¹H NMR (solvent) δppm 259 —CH₃ —H benzyl hydrochloride (DMSO-d₆) 1.44(3H, d, J = 6.8 Hz), 2.44-2.52(2H, m), 3.08-3.15(2H, m), 3.30-3.38(4H, m), 4.33(2H, brs), 4.55-4.62(1H, m), 6.51(1H, d, J = 6.3 Hz), 6.82(1H, d, J = 8.7 Hz). 6.97(2H, d, J = 8.7 Hz), 7.04(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.41(2H, d, J = 8.6 Hz), 7.45-7.47(4H, m), 7.57(2H, brs), 7.61(2H, d, J = 8.3 Hz), 7.69(2H, d, J = 8.4 Hz), 10.99(1H, brs). 260 —CH₃ —CH₃ benzyl free (CDCl₃) 1.58(3H, d, J = 6.9 Hz), 2.46(4H, brs), 2.72(3H, s), 3.46-3.53(6H, m), 4.97(1H, q, J = 6.9 Hz), 6.86(1H, d, J = 8.9 Hz), 7.07(2H, d, J = 8.6 Hz), 7.23(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.27-7.36(5H, m), 7.40(2H, d, J = 8.6 Hz), 7.43(2H, d, J = 7.3 Hz), 7.60(2H, d, J = 8.3 Hz), 7.82(1H, d, J = 3.3 Hz). 261 —CH₃ —CH₃ piperonyl free (CDCl₃) 1.58(3H, d, J = 6.9 Hz), 2.43(4H, brs), 2.72(3H, s), 3.44(2H, s), 3.48-3.68(4H, m), 4.97(1H, q, J = 6.9Hz), 5.95(2H, s), 6.74(2H, brs), 6.85(1 H, brs), 6.87(1H, d, J = 9.1 Hz), 7.07(2H, d, J = 8.7 Hz), 7.23(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.40(2H, d, J = 8.6 Hz), 7.43(2H, d, J = 7.9 Hz), 7.60(2H, d, J = 8.3 Hz), 7.82(1H, d, J = 3.1 Hz). 262 —CH₃ —H piperonyl hydrochloride (DMSO-d₆) 1.44(3H, d, J = 6.8 Hz), 2.49-2.52(2H, m), 3.01-3.06(2H, m), 3.29-3.45(4H, m), 4.23(2H, brs), 4.58-4.62(1H, m), 6.07(2H, s), 6.51(1H, d, J = 6.6 Hz), 6.82(1H, d, J = 8.7 Hz), 6.96-6.99(4H, m), 7.04(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.20(1H, brs), 7.41(2H, d, J = 8.6 Hz), 7.46(1H, d, J = 3.0 Hz), 7.61(2H, d, J = 8.3 Hz), 7.69(2H, d, J = 8.4 Hz). 10.99(1H, brs). 263 —H —C₂H₅ benzyl hydrochloride (DMSO-d₆) 1.14(3H, d, J = 6.9 Hz), 2.50-2.51(2H, m), 3.11(2H, brs), 3.35(4H, brs), 3.51(2H, q, J = 6.9 Hz), 4.33 (2H, brs), 4.63(2H, brs), 6.94(1H, d, J = 8.9 Hz), 7.03(2H, d, J = 8.6 Hz), 7.25(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.42-7.48(7H, m), 7.57(2H, brs), 7.62(1H, d, J = 3.1 Hz), 7.70(2H, d, J = 8.1 Hz), 11.03(1H, brs). 264 —H —C₂H₅ piperonyl hydrochloride (DMSO-d₆) 1.14(3H, d, J = 6.9 Hz), 2.50-2.51(2H, m), 3.06(2H, brs), 3.36(4H, brs), 3.52(2H, q, J = 6.9 Hz), 4.22 (2H, brs), 4.64(2H, brs), 6.07(2H, s), 6.94(1H, d, J = 8.9 Hz), 6.99(2H, brs), 7.03(2H, d, J = 8.6 Hz), 7.23(1H, brs), 7.25(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.42-7.49(4H, m), 7.62 (1H, d, J = 3.1 Hz), 7.71(2H, d, J = 8.1 Hz), 11.29(1H, brs).

TABLE 159

Example No. R₅₅₇ R₅₅₈ ¹H NMR (solvent) δppm 265 3,4-Cl₂PhCONH—

(CDCl₃) 2.39-2.49(4H, m), 3.39-3.79 (6H, m), 6.87(1H, d, J = 8.9 Hz), 7.06- 7.15(3H, m), 7.27-7.37(6H, m), 7.51(1H, d, J = 8.4 Hz), 7.74-7.78(1H, m), 8.01- 8.05(2H, m), 8.28(1H, d, J = 2.6 Hz), 9.10(1H, brs). 266 3,4-Cl₂PhCONH—

(CDCl₃) 2.37-2.48(4H, m), 3.43-3.75 (6H, m), 5.94(2H, s), 6.70-6.77(2H, m), 6.84(1H, brs), 6.92(1H, d, J = 8.9 Hz), 7.09-7.17(3H, m), 7.34-7.40(1H, m), 7.55(1H, d, J = 8.4 Hz), 7.73-7.77(1H, m), 8.04(1H, d, J = 2.1 Hz), 8.09(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.28(1H, d, J = 2.8 Hz), 8.63(1H, brs). 267 4-CF₃PhCH₂N(CH₃)—

(DMSO-d₆) 3.03-3.13(5H, m), 4.69- 4.75(3H, m), 6.88-6.98(3H, m), 7.06(2H, d, J = 8.6 Hz), 7.16- 7.23(2H, m), 7.33(1H, dd, J = 9.1 Hz, 3.1 Hz), 7.46(2H, d, J = 8.3 Hz), 7.69-7.73(3H, m), 7.91(2H, d, J = 8.7 Hz), 8.61(1H, d, J = 8.1 Hz), 10.35(1H, brs). 268 4-CF₃PhCH₂N(CH₃)—

(DMSO-d₆) 2.89-3.06(2H, m), 3.06(3H, s), 4.61-4.72(3H, m), 5.96(2H, s), 6.50 (1H, s), 6.84(1H, s), 6.97(1H, d, J = 8.9 Hz), 7.06(2H, d, J = 8.7 Hz), 7.33(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.46(2H, d, J = 8.1 Hz), 7.69-7.73(3H, m), 7.89(2H, d, J = 8.7 Hz), 8.56(1H, d, J = 8.3 Hz), 10.15 (1H, brs). 269 3,4-Cl₂PhCONH—

(CDCl₃) 2.28-2.30(2H, m), 2.58-2.60 (2H, m), 3.25-3.29(2H, m), 3.44(2H, s), 3.92-3.98(2H, m), 5.94(2H, s), 6.73(2H, s), 6.84(1H, s), 6.96(1H, d, J = 8.7 Hz), 7.14(1H, d, J = 7.8 Hz). 7.37(1H d, J = 7.8 Hz), 7.50-7.59(3H, m), 7.73(1H, dd, J = 8.2 Hz, 2.1 Hz), 7.83(1H, dd, J = 7.6 Hz, 3.0 Hz), 8.03(1H, d, J = 2.1 Hz). 8.06- 8.13(2H, m), 8.17(1H, s), 8.24(1H, d, J = 3.0 Hz).

TABLE 160

Example mp (° C.) or ¹H NMR No. R₅₅₉ R₅₆₀ Xb₁ Xb₂ R₅₆₁ Form (DMSO-d₆) δppm 270 —Cl —Cl —O—

piperonyl free ¹H NMR (at 375 K) 2.00(3H, brs), 2.30-2.38 (4H, m), 3.34-3.43(6H, m), 4.12(2H, s), 4.51 (2H, brs), 5.91(2H, s), 6.73(1H, d, J = 7.9 Hz), 6.77(1H, d, J = 7.9 Hz), 6.81(1H, s), 6.98(1H, d, J = 8.8 Hz), 7.05(2H, d, J = 8.2 Hz), 7.26(2H, d, J = 8.2 Hz), 7.73(1H, d, J = 8.4 Hz), 7.91(1H, dd, J = 2.1 Hz, 8.4 Hz), 8.12-8.18(3H, m), 8.48 (1H, d, J = 2.6 Hz), 10.17(1H, s). 271 —Cl —Cl —O—

benzyl free ¹H NMR (at 375 K) 2.00(3H, brs), 2.33-2.40 (4H, m), 3.38-3.42(4H, m), 3.49-3.53(2H, m), 4.13(2H, s), 4.51(2H, brs), 6.98(1H, d, J = 8.8 Hz), 7.02-7.10(2H, m), 7.16-7.30(7H, m), 7.73 (1H, d, J = 8.4 Hz), 7.91(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.11-8.17(2H, m), 8.48(1H, d, J = 2.5 Hz), 10.17(1H, s). 272 —CF₃ —H —O— —CH═CH— benzyl free ¹H NMR 2.39(4H, brs), 3.52(2H, s), 3.58(2H, (trans) brs), 3.71(2H, brs), 7.13(1H, d, J = 8.9 Hz), 7.14(2H, d, J = 8.7 Hz), 7.24(1H, d, J = 15.3Hz), 7.18-7.41(5H, m), 7.50(1H, d, J = 15.3 Hz), 7.76(2H, d, J = 8.7 Hz), 7.94(2H, d, J = 8.3 Hz), 8.17(2H, d, J = 8.3 Hz), 8.25(1H, dd, J = 8.9Hz, 2.7 Hz), 8.54(1H, d, J = 2.7 Hz), 10.66(1H, s). 273 —CF₃ —H —O— —CH═CH— piperonyl free ¹H NMR 2.37(4H, brs), 3.42(2H, s), 3.58(2H, (trans) brs), 3.70(2H, brs), 5.99(2H, s), 6.76(1H, dd, J = 8.0 Hz, 2.4 Hz), 6.85(1H, d, J = 8.0 Hz), 6.88 (1H, d, J = 1.5 Hz), 7.13(1H, d, J = 8.9 Hz), 7.14(2H, d, J = 8.7 Hz), 7.20(1H, d, J = 15.4 Hz), 7.50(1H, d, J = 15.4 Hz), 7.76(2H, d, J = 8.7 Hz), 7.94(2H, d, J = 8.2 Hz), 8.17(2H, d, J = 8.2 Hz), 8.25(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.54(1H, d, J = 2.6 Hz), 10.65(1H, s). 274 —CF₃ —H —N(CH₃)— none piperonyl dihydro- ¹H NMR 2.98-3.12(2H, m), 3.12-3.36(2H, m), chloride 3.50(3H, s), 3.71-4.68(6H, m), 6.06(2H, s), 6.93- 7.06(3H, m), 7.26(1H, s), 7.42(2H, d, J = 8.3 Hz), 7.53(2H, d, J = 8.3 Hz), 7.92(2H, d, J = 8.3 Hz), 8.12(1H, d, J = 9.2 Hz), 8.20(2H, d, J = 8.3 Hz), 8.67(1H, s), 10.79(1H, s), 11.47(1H, brs). 275 —CF₃ —H —N(CH₃)— none benzyl free mp 213-214

TABLE 161

Example mp (° C.) or ¹H NMR (CDCl₃) No. R₅₆₂ R₅₆₃ R₅₆₄ δppm 276 —Cl —Cl

¹H NMR 1.62-1.80(2H, m), 1.82-1.87(2H, m), 2.71(1H, dt, J = 3 Hz, 11.0 Hz), 2.84 (1H, brs), 2.94(1H, t, J = 11.0 Hz), 3.55-3.70(10H, m), 6.89(1H, d, J = 9.0 Hz), 6.93(2H, dd, J = 7.0 Hz, 2.0 Hz), 7.02 (2H, dd, J = 7.0 Hz, 2.0 Hz), 7.56(1H, d, J = 8.0 Hz), 7.71(1H, dd, J = 9.0 Hz, 2.0 Hz), 7.99(1H, d, J = 2.0 Hz), 8.10(1H, s), 8.15 (1H, dd, J = 9.0 Hz, 2.5 Hz), 8.25(1H, d, J = 2.5 Hz). 277 —Cl —Cl

¹H NMR 2.38-2.42(4H, m), 2.62-2.67(4H, m), 3.14-3.17(4H, m), 3.22(2H, s), 3.42 (2H, s), 3.61-3.63(4H, m), 5.95(2H, s), 6.70-6.75(2H, m), 7.03(2H, d, J = 8.0 Hz), 7.55(1H, d, J = 8.0 Hz), 7.70(1H, brs), 7.73(2H, d, J = 8.0 Hz), 8.01(1H, s), 8.15 (1H, brd, J = 9.0 Hz). 8.27(1H, d, J = 2.5 Hz). 278 —Cl —Cl

¹H NMR 2.40-2.45(4H, m), 2.60-2.64(4H, m), 3.13(4H, brs), 3.20(2H, brs). 3.48(2H, brs), 3.62(4H, brs), 6.85-6.91(3H, m), 7.01 (2H, d, J = 8.0 Hz), 7.26-7.32(5H, m), 7.52 (1H, d, J = 8.5 Hz), 7.70(1H, brs), 7.74(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.03(1H, d, J = 2.0 Hz). 8.15(1H, brd, J = 9.0, Hz), 8.29(1H, d, J = 2.5 Hz). 279 —H —CF₃

mp 180-183 280 —H —CF₃

mp 197-199 281 —H —CF₃

mp 133-135

TABLE 162

Example No. R₅₆₅ Form mp (° C.) 282

free 108-110 283

free 136-138 284

free 133-136 285

free 147-151 286

dihydrochloride 180-183 287

free 111-113 288

free 111-113 289

free 246-249 290

free 148-151 291

free 120-121

TABLE 163

Example No. R₅₆₆ Form mp (° C.) 292

free 83-86 293

free 130-133 294

free 145-146 295

trihydro- chloride 180-185 296

free 184-186 297

free 173-176 298

free 181-183 299

free 166-170

TABLE 164

Example No. R₅₆₇ mp (° C.) 300

102-104 301

106-109 302

261-264 303

173-175 304

164-166 305

158-160 306

174-176 307

206-207 308

165-166 309

164-167 310

188-190 311

130-132

TABLE 165

Example No. R₅₆₈ R₅₆₉ mp (° C.) or ¹H NMR (CDCl₃) δ ppm 312 —H

mp 166-167 313 —H

mp 157-158 314 —H

mp 218-219 315

benzyl ¹H NMR 0.25-0.31 (2H, m), 0.61- 0.69 (2H, m), 2.67-2.73 (1H, m), 2.86 (4H, brs), 3.18 (4H, brs), 3.83 (2H, s), 6.80-6.92 (3H, m), 7.16-7.62 (8H, m), 8.11 (2H, d, J = 8.1 Hz), 8.39 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.45 (1H, d, J = 2.5 Hz), 10.23 (1H, s), 10.93 (1H, brs). 316 —CONHPh benzyl ¹H NMR 3.07 (4H, brs), 3.26 (4H, brs), 3.98 (2H, s), 6.83-7.59 (14H, m), 7.65 (2H, d, J = 8.3 Hz), 8.06 (2H, d, J = 8.1 Hz), 8.37 (1H, d, J = 2.6 Hz), 8.49 (1H, dd, J = 8.9 Hz, 2.6 Hz), 9.30 (1H, s), 9.71 (1H, brs). 317

benzyl ¹H NMR 1.87 (4H, brs), 2.72 (4H, brs), 3.19 (4H, brs), 3.40 (4H, brs), 3.69 (2H, s), 6.58 (1H, d, J = 8.7 Hz), 6.80 (1H, s), 6.92 (1H, d, J = 9.2 Hz), 7.02 (1H, d, J = 8.9 Hz), 7.26-7.34 (5H, m), 7.57 (2H, d, J = 7.9 Hz), 7.90 (1H, d, J = 7.1 Hz), 8.05 (2H, d, J = 8.1 Hz), 8.40 (1H, s), 9.73 (1H, s).

TABLE 166

Example No. Xb₃ Xb₄ Xb₅ R₅₇₀ mp (° C.) or ¹H NMR (CDCl₃) δ ppm 318 —O—

benzyl mp 162-163 319 —O—

piperonyl mp 136-137 320 —O—

—O— none mp 176-177 321 —N(CH₃)—

benzyl ¹H NMR 2.43 (4H, brs), 2.67 (4H, t, J = 4.8 Hz), 3.22 (4H, t, J = 4.8 Hz), 3.24 (2H, s), 3.42 (3H, s), 3.52 (2H, s), 3.63 (4H, brs), 6.46 (1H, d, J = 9.1 Hz), 6.95 (2H, d, J = 8.9 Hz), 7.15 (2H, d, J = 8.9 Hz), 7.20-7.40 (5H, m), 7.65-7.80 (2H, m), 7.74 (2H, d, J = 8.2 Hz), 7.98 (2H, d, J = 8.2 Hz), 8.26 (1H, d, J = 2.5 Hz). 322 —N(CH₃)—

piperonyl ¹H NMR 2.41 (4H, brs), 2.67 (4H, t, J = 4.8 Hz), 3.22 (4H, t, J = 6.1 Hz), 3.24 (2H, s), 3.42 (5H, s), 3.62 (4H, t, J = 4.5 Hz), 5.94 (2H, s), 6.46 (1H, d, J = 9.1 Hz), 6.74 (2H, s), 6.85 (1H, s), 6.95 (2H, d, J = 8.9 Hz), 7.15 (2H, d, J = 8.9 Hz), 7.65-7.75 (1H, m), 7.74 (2H, d, J = 8.1 Hz), 7.83 (1H, brs), 7.99 (2H, d, J = 8.1 Hz), 8.26 (1H, d, J = 2.5 Hz). 323 —N(CH₃)—

benzyl ¹H NMR 1.31-1.52 (2H, m), 1.88 (2H, d, J = 12.3 Hz), 1.88-2.15 (1H, m), 2.29 (2H, d, J = 6.7 Hz), 2.44 (4H, t, J = 5.1 Hz), 2.76 (2H, t, J = 11.2 Hz), 3.42 (3H, s), 3.49 (2H, t, J = 4.9 Hz), 3.53 (2H, s), 3.59-3.78 (4H, m), 6.47 (1H, d, J = 9.1 Hz), 6.96 (2H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.9 Hz), 7.20-7.41 (5H, m), 7.61- 7.78 (2H, m), 7.75 (2H, d, J = 8.1 Hz), 7.98 (2H, d, J = 8.1 Hz), 8.25 (1H, d, J = 2.3 Hz). 324 —N(CH₃)—

piperonyl ¹H NMR 1.30-1.51 (2H, m), 1.88 (2H, d, J = 2.9 Hz), 1.98-2.11 (1H, m), 2.29 (2H, d, J = 6.7 Hz), 2.41 (4H, m), 2.76 (2H, t, J = 11.2 Hz), 3.42 (3H, s), 3.43 (2H, s), 3.49 (2H, t, J = 4.8 Hz), 3.55-3.78 (4H, m), 5.95 (2H, s), 6.47 (1H, d, J = 9.0 Hz), 6.74 (2H, s), 6.86 (1H, s), 6.96 (2H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.9 Hz), 7.70 (1H, brs), 7.71 (1H, dd, J = 9.0 Hz, 2.7 Hz), 7.75 (2H, d, J = 8.2 Hz), 7.99 (2H, d, J = 8.2 Hz), 8.26 (1H, d, J = 2.7 Hz).

TABLE 167

Example No. Xb₆ M R₅₇₁ Form δ mp (°C) or ¹H NMR 325 —N(Ac)— 1

hydro- chloride mp 214-216 326 —N(Ac)— 1

free ¹H NMR (DMSO-d₆) δ 1.77 (3H, s), 2.25-2.34 (4H, m), 3.30-3.50 (6H, m), 4.40 (2H, s), 6.97 (2H, d, J = 8.8 Hz), 7.22-7.35 (6H, m), 7.36 (2H, d, J = 8.8 Hz), 7.53- 7.59 (1H, m), 7.84 (1H, d, J = 8.3 Hz), 7.89-7.95 (2H, m), 8.20 (1H, d, J = 2.2 Hz), 10.61 (1H, s). 327 none 1

free mp 178-179 328 none 1 morpholino free mp 196-198 329 none 3

free mp 197-198 330 none 3 morpholino free mp 144-146 331 none 3

hydro- chloride mp 194-196 332 none 1

hydro- chloride mp 205-206 333 —S— 1

free ¹H NMR (CDCl₃) δ 2.35- 2.45 (4H, m), 3.42 (2H, s), 3.42-3.48 (2H, m), 3.58 (2H, brs), 3.65 (2H, s), 5.94 (2H, s), 6.72-6.75 (2H, m), 6.84 (1H, d, J = 1.1 Hz), 6.89 (2H, d, J = 8.8 Hz), 7.00-7.10 (1H, m), 7.19-7.25 (1H, m), 7.42 (2H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.65-7.76 (2H, m), 7.98 (1H, s), 7.99 (1H, s). 334 —SO— 1

free mp 133-135 335 —SO₂— 1

free mp 125-128 336 —CH═CH— (trans) 0

free mp 169-171

TABLE 168

Example No. R₅₇₂ R₅₇₃ ¹H NMR (solvent) δ ppm 337 4-CF₃Ph— benzyl (CDCl₃) 2.30-2.34 (2H, m), 2.39 2.43 (2H, m), 3.46-3.49 (4H, m), 3.62-3.66 (2H, m), 3.69 (2H, s), 6.94 (1H, d, J = 8.7 Hz), 7.03-7.08 (2H, m), 7.19-7.35 (7H, m), 7.75 (2H, d, J = 8.2 Hz), 8.00 (2H, d, J = 8.2 Hz), 8.21 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.26 (1H, s), 8.29 (1H, d, J = 2.8 Hz). 338 4-CF₃Ph— piperonyl (CDCl₃) 2.28-2.32 (2H, m), 2.36-2.39 (2H, m), 3.39 (2H, s), 3.45-3.49 (2H, m), 3.60-3.64 (2H, m), 3.68 (2H, s), 5.94 (2H, s), 6.69-6.76 (2H, m), 6.83 (1H, brs), 6.92 (1H, d, J = 8.7 Hz), 7.01- 7.06 (2H, m), 7.17-7.22 (2H, m), 7.72 (2H, d, J = 8.4 Hz), 8.00 (2H, d, J = 8.1 Hz), 8.17-8.21 (1H, m), 8.29 (1H, d, J = 2.6 Hz), 8.49 (1H, brs). 339 3,4-Cl₂Ph— benzyl (CDCl₃) 2.31-2.34 (2H, m), 2.38-2.42 (2H, m), 3.46-3.50 (4H, m), 3.62-3.65 (2H, m), 3.69 (2H, s), 6.90 (1H, d, J = 8.9 Hz), 7.00-7.05 (2H, m), 7.17-7.23 (2H, m), 7.28-7.35 (5H, m), 7.54 (1H, d, J = 8.2 Hz). 7.73 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.99 (1H, d, J = 2.1 Hz), 8.12-8.17 (1H, m), 8.28 (1H, d, J = 2.8 Hz), 8.44 (1H, brs). 340 3,4-Cl₂Ph— 3-pyridyl (CDCl₃) 3.02-3.06 (2H, m), 3.13-3.17 (2H, m), 3.63-3.67 (2H, m), 3.76-3.82 (4H, m), 6.91 (1H, d, J = 8.9 Hz), 7.02-7.07 (2H, m), 7.17-7.24 (4H, m), 7.52 (1H, d, J = 8.4 Hz), 7.73-7.76 (1H, m), 8.01 (1H, d, J = 2.0 Hz), 8.11-8.13 (1H, m), 8.18 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.23-8.25 (2H, m), 8.95 (1H, brs). 341 3,4-Cl₂Ph— piperonyl (CDCl₃) 2.28-2.39 (4H, m), 3.39 (2H, s), 3.46- 3.49 (2H, m), 3.60-3.64 (2H, m), 3.69 (2H, s), 5.94 (2H, s), 6.69-6.76 (2H, m), 6.82-6.83 (1H, m), 6.89 (1H, d, J = 8.9 Hz), 6.99-7.04 (2H, m), 7.15-7.21 (2H, m), 7.53 (1H, d, J = 8.4 Hz). 7.71- 7.75 (1H, m), 7.99 (1H, d, J = 2.1 Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.28 (1H, d, J = 2.6 Hz), 8.56 (1H, s). 342 3,4-Cl₂PhNH— piperonyl (DMSO-d₆) 2.20-2.35 (4H, m), 3.38 (2H, s), 3.40- 3.55 (4H, m), 3.69 (2H, s), 5.98 (2H, s), 6.70- 6.76 (1H, m), 6.76-6.86 (2H, m), 6.97-7.00 (3H, m), 7.02-7.24 (2H, m), 7.35 (1H, dd, J = 8.8 Hz, 2.5 Hz), 7.52 (1H, d, J = 8.8 Hz), 7.86 (1H, d, J = 2.5 Hz), 7.98 (1H, dd, J = 5.8 Hz, 2.8 Hz), 8.19 (1H, d, J = 2.6 Hz), 8.89 (1H, s), 9.08 (1H, s).

TABLE 169

Example No. R₅₇₄ ¹H NMR (DMSO-d₆) δ ppm or MS 343 —H ¹H NMR 2.33 (2H, t, J = 7.7 Hz), 2.77 (2H, t, J = 7.7 Hz), 6.75 (1H, brs), 6.87 (2H, d, J = 8.6 Hz), 7.15-7.23 (3H, m), 7.28 (1H, brs), 7.54 (1H, d, J = 8.7 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.21 (1H, d, J = 20 Hz), 10.57 (1H, s). 344 —CH₃ MS 460 (M⁺) 345 —C₂H₅ ¹H NMR 0.97 (3H, t, J = 7.2 Hz), 2.32 (2H, t, J = 7.8 Hz), 2.77 (2H, t, J = 7.8 Hz), 3.00-3.08 (2H, m), 6.87 (2H, d, J = 8.6 Hz), 7.14-7.21 (3H, m), 7.54 (1H, d, J = 9.8 Hz) 7.78 (1H, brt), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.3 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21(1H, d, J = 2.1 Hz), 10.57 (1H, s). 346 —CH(CH₃)₂ ¹H NMR 1.00 (6H, d, J = 6.6 Hz), 2.30 (2H, t, J = 7.7 Hz), 2.77 (2H, t, J = 7.7 Hz), 3.75-3.86 (1H, m), 6.87 (2H, d, J = 8.6 Hz), 7.13-7.20 (3H, m), 7.54 (1H, d, J = 8.9 Hz), 7.65 (1H, brd), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.1 Hz, 2.5 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.1 Hz), 10.58 (1H, s). 347 —CH₂CH(CH₃)₂ ¹H NMR 0.78 (6H, d, J = 6.7 Hz), 1.56-1.68 (1H, m), 2.36 (2H, t, J = 7.6 Hz), 2.78 (2H, t, J = 7.6 Hz), 2.81-2.82 (2H, m), 6.87 (2H, d, J = 8.6 Hz), 7.10-7.22 (3H, m), 7.51 (1H, d, J = 8.9 Hz), 7.77 (1H, brt), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 10.57 (1H, s). 348 —(CH₂)₃CH₃ ¹H NMR 0.84 (3H, t, J = 7.3 Hz), 1.15-1.27 (2H, m), 1.27- 1.38 (2H, m), 2.33 (2H, t, J = 7.7 Hz), 2.77 (2H, t, J = 7.7 Hz), 2.97-3.05 (2H, m), 6.87 (2H, d, J = 8.6 Hz), 7.11-7.21 (3H, m), 7.50-7.58 (1H, m), 7.74 (1H, brt), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 10.57 (1H, s). 349 cyclopropyl ¹H NMR 0.26-0.37 (2H, m), 0.51-0.63 (2H, m), 2.29 (2H, t, J = 7.7 Hz), 2.53-2.61 (1H, m), 2.76 (2H, t, J = 7.7 Hz), 6.87 (2H, d, J = 8.6 Hz), 7.10-7.23 (3H, m), 7.54 (1H, d, J = 8.6 Hz), 7.80-8.00 (4H, m), 8.21 (1H, d, J = 2.1 Hz), 10.57 (1H, s). 350 cyclopentyl ¹H NMR 1.21-1.34 (2H, m), 1.41-1.51 (2H, m), 1.51-1.63 (2H, m), 1.68-1.80 (2H, m), 2.31 (2H, t, J = 7.7 Hz), 2.76 (2H, t, J = 7.7 Hz), 3.90-3.99 (1H, m), 6.87 (2H, d, J = 8.6 Hz), 7.14- 7.21 (3H, m), 7.50-7.57 (1H, m), 7.72 (1H, brd), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.91 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.1 Hz), 10.58 (1H, s). 351 cyclohexyl ¹H NMR 1.00-1.15 (3H, m), 1.15-1.28 (2H, m), 1.48-1.58 (1H, m), 1.58-1.70 (4H, m), 2.31 (2H, t, J = 7.6 Hz), 2.77 (2H, t, J = 7.6 Hz), 3.44-3.53 (1H, m), 6.87 (2H, d, J = 8.6 Hz), 7.11- 7.23 (3H, m), 7.50-7.57 (1H, m), 7.62 (1H, brd), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.04 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 10.57 (1H, s).

TABLE 170

Example No. R₅₇₅ ¹H NMR (DMSO-d₆) δ ppm 352 cycloheptyl 1.28-1.40 (4H, m), 1.40-1.61 (6H, m), 1.63-1.77 (2H, m), 2.31 (2H, t, J = 7.6 Hz), 2.76 (2H, t, J = 7.6 Hz), 3.64- 3.74 (1H, m), 6.87 (2H, d, J = 8.6 Hz), 7.11-7.23 (3H, m), 7.54 (1H, d, J = 9.1 Hz), 7.67 (1H, brd), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 10.57 (1H, s). 353 cyclooctyl 1.30-1.65 (14H, m), 2.31 (2H, t, J = 7.6 Hz), 2.76 (2H, t, J = 7.6 Hz), 3.69-3.80 (1H, m), 6.87 (2H, d, J = 8.6 Hz), 7 10-7.22 (3H, m), 7.54 (1H, d, J = 8.9 Hz), 7.65 (1H, brd), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.3 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.21 (1H, d, J = 2.0 Hz), 10.57 (1H, s). 354 cyclododecanyl 1.10-1.41 (20H, m), 1.41-1.54 (2H, m), 2.32 (2H, t, J = 7.5 Hz), 2.77 (2H, t, J = 7.5 Hz), 3.79-3.88 (1H, m), 6.86 (2H, d, J = 8.6 Hz), 7.10-7.21 (3H, m), 7.48-7.57 (2H, m), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.1 Hz, 2.5 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 10.58 (1H, s). 355 cyclopropylmethyl 0.06-0.16 (2H, m), 0.28-0.42 (2H, m), 0.78-0.90(1H, m), 2.35 (2H, t, J = 7.7 Hz), 2.78 (2H, t, J = 7.7 Hz), 2.84- 2.97 (2H, m), 6.87 (2H, d, J = 8.5 Hz), 7.12-7.27 (3H, m), 7.54 (1H, d, J = 8.8 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.87 (1H, brt), 7.89 (1H, dd, J = 13.2 Hz, 2.3 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.21 (1H, d, J = 2.0 Hz), 10.57 (1H, s). 356 cyclohexylmethyl 0.71-0.86 (2H, m), 1.03-1.20 (3H, m), 1.22-1.34 (1H, m) 1.50-1.69 (5H, m), 2.35 (2H, t, J = 7.6 Hz), 2.78 (2H, t, J = 7.6 Hz), 2.80-2.90 (2H, m), 6.86 (2H, d, J = 8.6 Hz) 7.12- 7.23 (3H, m), 7.54 (1H, d, J = 8.9 Hz), 7.73 (1H, brt), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 10.57 (1H, s). 357 piperonyl 2.41 (2H, t, J = 7.6 Hz), 2.81 (2H, t, J = 7.6 Hz), 4.15 (2H, d, J = 5.9 Hz), 5.96 (2H, s), 6.63(1H, d, J = 8.0 Hz), 6.74 (1H, d, J = 1.4 Hz), 6.80 (1H, d, J = 8.0 Hz), 6.87 (2H, d, J = 8.8 Hz), 7.14-7.23 (3H, m), 7.54 (1H, d, J = 9.8 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.89(1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.1 Hz), 8.25 (1H, brt), 8.40-8.46 (2H, m), 10.58 (1H, s). 358 —CH(CH₃)Ph 1.30 (3H, d, J = 7.0 Hz), 2.40 (2H, t, J = 7.5 Hz), 2.78 (2H, t, J = 7.5 Hz), 3.86-3.96 (1H, m), 6.82-6.99 (2H, m), 7.12- 7.24 (6H, m), 7.24-7.31 (2H, m), 7.55 (1H, dd, J = 8.9 Hz, 1.2 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.5 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.1 Hz), 8.24 (1H, brd), 10.59 (1H, s).

TABLE 171

Example No. R₅₇₆ ¹H NMR (DMSO-d₆) δ ppm or MS 359 2-pyridylmethyl MS 537 (M⁺) 360 3-pyridylmethyl ¹H NMR 2.44 (2H, t, J = 7.6 Hz), 2.82 (2H, t, J = 7.6 Hz), 4.27 (2H, d, J = 5.9 Hz), 6.86 (2H, dd, J = 6.7 Hz, 1.9 Hz), 7.14-7.22 (3H, m), 7.25-7.32 (1H, m), 7.46- 7.58 (2H, m), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.5 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.1 Hz), 8.38 (1H, brt), 8.40- 8.46 (2H, m), 10.58 (1H, s). 361 4-pyridylmethyl MS 537 (M⁺) 362 —(CH₂)₂NHAc ¹H NMR 1.78 (3H, s), 2.34 (2H, t, J = 7.8 Hz), 2.78 (2H, t, J = 7.8 Hz), 2.96-3.10 (4H, m), 6.83- 6.91 (2H, m), 7.14-7.23 (3H, m), 7.54 (1H, dd, J = 8.9 Hz, 1.3 Hz), 7.80-7.98 (5H, m), 8.21(1H, d, J = 2.1 Hz), 10.58 (1H, s). 363 —CH(CH₃)(CH₂)₄CH₃ ¹H NMR 0.84 (3H, t, J = 7.0 Hz), 0.96 (3H, d, J = 6.6 Hz), 1.08-1.34 (8H, m), 2.32 (2H, t, J = 7.2 Hz), 2.77 (2H, t, J = 7.2 Hz), 3.65-3.76 (1H, m), 6.82- 6.89 (2H, m), 7.12-7.21 (3H, m), 7.50-7.60 (2H, m), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.5 Hz), 7.94 (1H, dd, J = 8.3 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 10.58 (1H, s). 364 —(CH₂)₂OCH₃ ¹H NMR 2.35 (2H, t, J = 7.7 Hz), 2.77 (2H, t, J = 7.7 Hz), 3.13-3.22 (2H, m), 3.22 (3H, s), 3.29 (2H, t, J = 5.8 Hz), 6.82-6.92 (2H, m), 7.13-7.23 (3H, m), 7.54 (1H, d, J = 8.9 Hz) 7.85 (1H, d, J = 8.4 Hz), 7.85- 7.92 (2H, m), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.21 (1H. d. J = 2.0 Hz), 10.57 (1H, s). 365

MS 554 (M⁺) 366

MS 619 (M⁺)

TABLE 172

Ex- am- ple No. R₅₇₇ R₅₇₈ mp (° C.) or MS 367 —H morpholino mp 160-162 368 —F morpholino mp 150-151 369 —F

MS 657 (M⁺ + H) 370 —F

MS 646 (M⁺ − 1) 371 —F 4-CH₃OPh(CH₂)₂N(C₂H₅)— MS 608 (M⁺) 372 —F 4-CH₃OPhCH₂N(C₂H₅)— MS 594 (M⁺) 373 —F 3,4-(CH₃O)₂PhCH₂N(CH₂CH₂CH₃)— MS 638 (M⁺)

TABLE 173

Example No. R₅₇₉ ¹H NMR (DMSO-d₆) δ ppm 374 Ph— 2.39-2.49 (2H, m), 2.78-2.88 (2H, m), 4.18-4.30 (2H, m), 6.87 (2H, d, J = 8.6 Hz), 7.02-7.33 (8H, m), 7.55 (1H, d, J = 8.9 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.22 (1H, d, J = 2.0 Hz), 8.32 (1H, brt), 10.58 (1H, s). 375 4-FPh— 2.43 (2H, t, J = 7.6 Hz), 2.82 (2H, t, J = 7.6 Hz), 4.22 (2H, d, J = 5.9 Hz) 6.87 (2H, d, J = 8.6 Hz), 7.04-7.12 (2H, m), 7.12- 7.24 (5H, m) 7.55 (1H, d, J = 9.0 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J =13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.1 Hz), 8.32 (1H, brt), 10.58 (1H, s). 376 3,4-(CH₃O)₂Ph— 2.42 (2H, t, J = 7.6 Hz), 2.82 (2H, t, J = 7.6 Hz), 3.70 (3H, s), 3.71 (3H, s), 4.18 (2H, d, J = 5.8 Hz), 6.67 (1H, d, J = 8.4 Hz), 6.77-6.90 (4H, m), 7.15-7.23 (3H, m), 7.55 (1H, d, J = 9.0 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.0 Hz), 8.25 (1H, brt), 11.58 (1H, s). 377 2-ClPH— 2.48 (2H, t, J = 7.5 Hz), 2.83 (2H, t, J = 7.5 Hz), 4.30 (2H, d, J = 5.9 Hz), 6.88 (2H, d, J = 8.6 Hz), 7.08-7.15 (1H, m), 7.15- 7.32 (5H, m), 7.38-7.46 (1H, m), 7.51-7.59 (1H, m), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.0 Hz), 8.34 (1H, brt), 10.58 (1H, s). 378 3-ClPH— 2.45 (2H, t, J = 7.5 Hz), 2.83 (2H, t, J = 7.5 Hz), 4.25 (2H, d, J = 6.0 Hz), 6.87 (2H, d, J = 8.6 Hz), 7.07-7.12 (1H, m), 7.12- 7.21 (3H, m), 7.21-7.25 (1H, m), 7.25-7.33 (2H, m), 7.55 (1H, d, J = 9.0 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.1 Hz), 8.37 (1H, brt), 10.58 (1H, s). 379 4-ClPh— 2.44 (2H, t, J = 7.5 Hz), 2.82 (2H, t, J = 7.5 Hz), 4.22 (2H, d, J = 6.0 Hz), 6.87 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.4 Hz), 7.16-7.22 (3H, m), 7.29-7.34 (2H, m), 7.55 (1H, d, J = 8.1 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.5 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 8.34 (1H, brt), 10.58 (1H, s). 380 2-CH₃Ph— 2.21 (3H, s), 2.44 (2H, t, J = 7.5 Hz), 2.82 (2H, t, J = 7.5 Hz), 4.21 (2H, d, J = 5.7 Hz), 6.87 (2H, d, J = 8.6 Hz), 7.00-7.07 (1H, m), 7.07-7.23 (6H, m), 7.55 (1H, d, J = 9.0 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.16 (1H, brt), 8.22 (1H, d, J = 2.1 Hz), 10.58 (1H, s). 381 4-CH₃OPh— 2.41 (2H, t, J = 7.6 Hz), 2.81 (2H, t, J = 7.6 Hz), 3.71 (3H, s), 4.17 (2H, d, J = 5.8 Hz), 6.80-6.91 (4H, m), 7.07 (2H, d, J = 8.5 Hz), 7.13-7.25 (3H, m), 7.55 (1H, d, J = 8.5 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 8.24 (1H, brt), 10.58 (1H, s).

TABLE 174

Example No. R₅₈₀ ¹H NMR (DMSO-d₆) δ ppm 382 Ph— 2.33 (2H, t, J = 7.7 Hz), 2.66 (2H, t, J = 7.3 Hz), 2.77 (2H, t, J = 7.7 Hz), 3.20-3.29 (2H, m), 6.87 (2H, d, J = 8.6 Hz), 7.12-7.22 (6H, m), 7.23-7.30 (2H, m), 7.54 (1H, dd, J = 8.9 Hz, 1.1 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.85-7.91 (2H, m), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 10.57 (1H, s). 383 4-FPh— 2.33 (2H, t, J = 7.7 Hz), 2.65 (2H, t, J = 7.2 Hz), 2.76 (2H, t, J = 7.7 Hz), 3.30-3.37 (2H, m), 6.87 (2H, d, J = 8.5 Hz), 7.04-7.11 (2H, m), 7.13-7.22 (5H, m), 7.54 (1H, d, J = 9.1 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.80-7.92 (2H, m), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.21 (1H, d, J = 2.0 Hz), 10.58 (1H, s). 384 4-ClPh— 2.32 (2H, t, J = 7.6 Hz), 2.66 (2H, t, J = 7.1 Hz), 2.76 (2H, t, J = 7.6 Hz), 3.18-3.27 (2H, m), 6.87 (2H, d, J = 8.5 Hz), 7.10-7.22 (5H, m), 7.31 (2H, d, J = 8.3 Hz), 7.54 (1H, d, J = 8.9 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.85-7.92 (2H, m), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.21 (1H, d, J = 2.0 Hz), 10.57 (1H, s). 385 3-CH₃OPh— 2.33 (2H, t, J = 7.7 Hz), 2.64 (2H, t, J = 7.3 Hz), 2.78 (2H, t, J = 7.7 Hz), 3.18-3.27 (2H, m), 3.72 (3H, s), 6.70- 6.78 (3H, m), 6.87 (2H, d, J = 8.6 Hz), 7.12-7.23 (4H, m), 7.54 (1H, dd, J = 8.9 Hz, 1.2 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.85-7.92 (2H, m), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.0 Hz), 10.57 (1H, s). 386 4-CH₃OPh— 2.33 (2H, t, J = 7.6 Hz), 2.59 (2H, t, J = 7.2 Hz), 2.77 (2H, t, J = 7.6 Hz), 3.16-3.24 (2H, m), 3.71 (3H, s), 6.83 (2H, d, J = 8.5 Hz), 6.87 (2H, d, J = 8.5 Hz), 7.07 (2H, d, J = 8.4 Hz), 7.13-7.23 (3H, m), 7.54 (1H, d, J = 8.5 Hz), 7.80- 7.98 (4H, m), 8.21 (1H. d, J = 1.8 Hz), 10.57 (1H, s). 387 PhO— 2.38 (2H, t, J = 7.7 Hz), 2.79 (2H, t, J = 7.7 Hz), 3.38- 3.43 (2H, m), 3.94 (2H, t, J = 5.7 Hz), 6.79-6.85 (2H, m), 6.89-6.96 (3H, m), 7.12-7.20 (3H, m), 7.23-7.31 (2H, m), 7.50-7.57 (1H, m), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 8.10 (1h, brt), 8.22 (1H, d, J = 2.1 Hz), 10.58 (1H, s). 388 PhCH₂— 1.60-1.70 (2H, m), 2.36 (2H, t, J = 7.4 Hz), 2.49-2.55 (2H, m), 2.79 (2H, t, J = 7.4 Hz), 3.00-3.08 (2H, m), 6.83- 6.90 (2H, m), 7.10-7.21 (6H, m), 7.21-7.29 (2H, m), 7.53 (1H, d, J = 8.9 Hz), 7.89-7.92 (3H, m), 8.21 (1H, d, J = 2.1 Hz). 10.57 (1H, s).

TABLE 175

Example No. R₅₈₁ MS 389 —CHPh₂ 681 (M⁺ + 1) 390 —NHCOPh 633 (M⁺) 391 —O(CH₂)₂Ph 634 (M⁺) 392 —(CH₂)₂N(CH₃)Ph 647 (M⁺) 393

675 (M⁺) 394 morpholino 599 (M⁺) 395

626 (M⁺) 396 cyclohexyl 596 (M⁺) 397

656 (M⁺) 398

626 (M⁺) 399 4-CH₃OPhCONH— 664 (M⁺ + 1) 400

644 (M⁺) 401

620 (M⁺ − 1) 402

623 (M⁺ + 2)

TABLE 176

Example No. R₅₈₂ R₅₈₃ Property 403 —H 4-CF₃OPhNH—  mp 91-95° C. 404 —F 4-CF₃OPhNH— mp 145-147° C. 405 —H 4-CF₃PhO— mp 118-121° C. 406 —H 4-CF₃OPhO— mp 126-127° C. 407 —F 4-CF₃PhO— mp 129-134° C. 408 —H 4-CNPhO— mp 148-149° C. 409 —F 4-CNPhO— mp 147-150° C. 410 —F 4-CF₃OPhO— ¹H NMR (CDCl₃) δ 1.69-1.85 (4H, m), 2.62 (2H, t, J = 7.5 Hz), 2.90 (2H, t, J = 7.5 Hz), 3.36 (1H, m), 3.57-3.67 (3H, m), 4.47 (1H, m), 6.85- 6.90 (4H, m), 7.00 (1H, t, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.13 (2H, d, J = 8.5 Hz), 7.30 (1H, brd, J = 8.5 Hz), 7.52 (1H, d, J = 8.5 Hz), 7.69-7.75 (2H, m), 7.98 (1H, d, J = 2.0 Hz), 8.80 (1H, s). 411 —F PhO— MS 606 (M⁺) 412 —F 4-ClPhCH₂— MS 638 (M⁺) 413 —F 4-CH₃PhCH₂— MS 618 (M⁺) 414 —F 4-ClPh— MS 626 (M⁺) 415 —F Ph— MS 590 (M⁺) 416 —F 2-NH₂PhCO— MS 633 (M⁺)

TABLE 177

Example No. R₅₈₄ R₅₈₅ Form mp (° C.) or MS 417 —F —H free MS 543 (M⁺) 418 —F —(CH₂)₂OPh free MS 664 (M⁺ + H) 419 —F —(CH₂)₂Ph free MS 648 (M⁺ + H) 420 —F —(CH₂)₂N(C₂H₅)₂ free MS 643 (M⁺ + H) 421 —H —(CH₂)₂Ph fumarate mp 148-151 422 —F —(CH₂)₃Ph free MS 661 (M⁺) 423 —F —(CH₂)₂CHPh₂ free MS 737 (M⁺) 424 —F

free MS 638 (M⁺) 425 —F 4-CH₃SPh(CH₂)₂— free MS 692 (M⁺ − 1) 426 —F 4-CH₃PhO(CH₂)₂— free MS 678 (M⁺ + H) 427 —F

free MS 723 (M⁺ + H) 428 —F 4-CH₃OPh(CH₂)₄— free MS 705 (M⁺) 429 —F

free MS 658 (M⁺ + H) 430 —F 4-CH₃Ph(CH₂)₂— free MS 661 (M⁺) 431 —F —(CH₂)₂N(CH₃)Ph free MS 676 (M⁺) 432 —F

free MS 653 (M⁺)

TABLE 178

Example No. R₅₈₆ R₅₈₇ R₅₈₈ R₅₈₉ R₅₉₀ mp (° C.) or MS 433 —H —H —H —CF₃ —H mp 124-126 434 —F —H —H —CF₃ —H mp 132-134 435 —F —H —H —Cl —H MS 654 (M⁺) 436 —F —F —H —H —H MS 638 (M⁺) 437 —F —H —H —H —H MS 620 (M⁺) 438 —F —H —H —OCH₃ —H MS 651 (M⁺ + H) 439 —F —H —Cl —H —H MS 656 (M⁺) 440 —F —Cl —H —H —H MS 654 (M) 441 —F —H —Cl —Cl —H MS 690 (M⁺) 442 —F —H —OCH₃ —H —H MS 650 (M⁺) 443 —F —H —OCH₃ —H —OCH₃ MS 680 (M⁺) 444 —F —H —H —CH₃ —H MS 635 (M⁺ + H) 445 —F —H —CH₃ —H —H MS 636 (M⁺ + 2) 446 —F —CH₃ —H —H —H MS 635 (M⁺ + H) 447 —F —H —CH₃ —CH₃ —H MS 648 (M⁺) 448 —F —H —H —F —H MS 638 (M⁺) 449 —F —H —F —H —H MS 638 (M⁺) 450 —F —H —F —H —F MS 656 (M⁺) 451 —F —CF₃ —H —H —H MS 656 (M⁺) 452 —F —H —H —OCF₃ —H MS 705 (M⁺ + H) 453 —F —H —OCF₃ —H —H MS 704 (M⁺) 454 —F —OCF₃ —H —H —H MS 704 (M⁺) 455 —F —H —Cl —OCH₃ —H MS 685 (M⁺ + H)

TABLE 179

Example No. R₅₉₁ R₅₉₂ Property 456 —H —CH₂CONHPh ¹H NMR (CDCl₃) δ 2.45 (2H, brt, J = 5.0 Hz), 2.55 (2H, brt, J = 5.0 Hz), 2.63 (2H, t, J = 7.5 Hz), 2.96 (2H, t, J = 7.5 Hz), 3.11 (2H, s), 3.47 (2H, brs), 3.70 (2H, brs), 6.93 (2H, d, J = 8.5 Hz), 6.98 (2H, d, J = 8.5 Hz), 7.13 (1H, t, J = 8.5 Hz), 7.15 (2H, d, J = 8.5 Hz), 7.34 (2H, t, J = 8.5 Hz), 7.52-7.59 (5H, m), 7.73 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.99 (1H, d, J = 2.0 Hz), 8.28 (1H, s), 8.92 (1H, s). 457 —F —CH₂CONHPh ¹H NMR (CDCl₃) δ 2.39 (2H, brs), 2.51 (2H, brs), 2.61 (2H, t, J = 7.5 Hz), 2.93 (2H, t, J = 7.5 Hz), 3.08 (2H, s), 3.43 (2H, brs), 3.67 (2H, brs), 6.88 (2H, d, J = 8.5 Hz), 7.03 (1H, t, J = 8.5 Hz), 7.11-7.15 (3H, m), 7.30-7.35 (3H, m), 7.51- 7.54 (3H, m), 7.70 (1H, dd, J = 9.0 Hz, 2.0 Hz), 7.74 (1H, dd, J = 8.5 Hz, 2.0 Hz), 8.00 (1H, d, J = 2.0 Hz), 8.74 (1H, s), 8.93 (1H, s). 458 —F —(CH₂)₃Ph MS 633 (M⁺) 459 —F —(CH₂)₄Ph MS 647 (M⁺) 460 —F —CH(C₂H₅)₂ MS 586 (M⁺ + 1) 461 —F —CH(CH₃)₂ MS 556 (M⁺ − 1) 462 —F —(CH₂)₃CH₃ MS 571 (M⁺) 463 —F —(CH₂)₂N(CH₃)₂ MS 585 (M⁺ −1) 464 —F —COOC(CH₃)₃ mp 155-157° C. 465 —F —CH₂COPh MS 633 (M⁺) 466 —H 3-pyridyl mp 153-155° C. 467 —F 3-pyridyl mp 183-185° C. 468 —F 2-pyridyl MS 591 (M⁺ − 1) 469 —F 4-pyridyl MS 592 (M⁺) 470 —F

MS 593 (M⁺) 471 —F

MS 593 (M⁺)

TABLE 180

Exam- ple No. R₅₉₃ R₅₉₄ MS 472 —CH₃ benzyl 619 (M⁺) 473 2-pyridylmethyl —H 606 (M⁺) 474 3-pyridylmethyl —H 606 (M⁺) 475 4-pyridylmethyl —H 605 (M⁺ − 1) 476 cyclopentyl —H 583 (M⁺) 477 cycloheptyl —H 611 (M⁺) 478

—H 612 (M⁺) 479

—H 627 (M⁺ + H) 480

—H 628 (M⁺) 481

—H 612 (M⁺) 482 2-quinolylmethyl —H 657 (M⁺ + H) 483

—H 686 (M⁺ − H) 484

—H 625 (M⁺) 485

—H 688 (M⁺)

TABLE 181

Example No. R₅₉₅ R₅₉₆ R₅₉₇ Form mp (° C.) or MS 486 —H —H —COOC(CH₃)₃ free mp 188-189 487 —H —H —CH₃ free mp 189-191 488 —H —H benzyl fumarate mp 190-192 489 —F —H —(CH₂)₂Ph hydrochloride mp 191-200 490 —F —H piperonyl hydrochloride mp 226-228 491 —F —H

free MS 714 (M⁺ − 1) 492 —F —H 1-naphthylmethyl free MS 655 (M⁺) 493 —F —CH₃ 3,4-(CH₃O)₂PhCH₂— free MS 679 (M⁺) 494 —F —H

free MS 678 (M⁺ + 1) 495 —F —H —CH(CH₃)Ph free MS 619 (M⁺) 496 —F —H

free MS 682 (M⁺) 497 —F —H (4-FPh)₂CH— free MS 717 (M⁺) 498 —F —H 4-CH₃OPhCH(Ph)— free MS 711 (M⁺)

TABLE 182

Example No. R₅₉₈ R₅₉₉ R₆₀₀ R₆₀₁ R₆₀₂ Form mp (° C.) or MS 499 —F —H —H —OCF₃ —H hydrochloride mp 118-121 500 —F —H —H —CN —H free mp 190-192 501 —H —H —H —OCF₃ —H hydrochloride mp 148-149 502 —H —H —H —CN —H free mp 186-188 503 —F —CF₃ —H —H —H free MS 659 (M⁺) 504 —F —H —CF₃ —H —H free MS 659 (M⁺) 505 —F —H —H —COOC(CH₃)₃ —H free MS 691 (M⁺) 506 —F —H —H —F —H free MS 609 (M⁺) 507 —F —OCH₃ —H —H —H free MS 621 (M⁺) 508 —F —Cl —H —H —H free MS 625 (M⁺) 509 —F —H —H —Cl —H free MS 627 (M⁺) 510 —F —H —Cl —H —H free MS 625 (M⁺) 511 —F —Cl —Cl —H —H free MS 661 (M⁺) 512 —F —H —H —OCH₃ —H free MS 621 (M⁺) 513 —F —H —OCH₃ —H —H free MS 621 (M⁺) 514 —F —H —H —CH₃ —H free MS 605 (M⁺) 515 —F —H —CH₃ —H —H free MS 605 (M⁺) 516 —F —CH₃ —H —H —H free MS 605 (M⁺) 517 —F —CH₃ —CH₃ —H —H free MS 619 (M⁺) 518 —F —H —CH₃ —CH₃ —H free MS 619 (M⁺) 519 —F —H —H —CF₃ —H free MS 659 (M⁺) 520 —F —H —H —Ph —H free MS 667 (M⁺) 521 —F —F —H —H —H free MS 609 (M⁺) 522 —F —F —H —F —H free MS 627 (M⁺) 523 —F —OCH₃ —H —H —Cl free MS 657 (M⁺)

TABLE 183

Example No. R₆₀₃ R₆₀₄ R₆₀₅ R₆₀₆ R₆₀₇ Form mp (° C.) or MS 524 —H —H —H —H —H fumarate mp 168-170 525 —H —H —Cl —H —H free MS 638 (M⁺ − 1) 526 —H —Cl —H —H —H free MS 639 (M⁺) 527 —Cl —H —H —H —H free MS 641 (M⁺ + 2) 528 —Cl —Cl —H —H —H free MS 675 (M⁺ + 2) 529 —Cl —H —Cl —H —H free MS 673 (M⁺) 530 —Cl —H —H —Cl —H free MS 673 (M⁺) 531 —H —Cl —Cl —H —H free MS 676 (M⁺ + 3) 532 —H —OCH₃ —H —H —H free MS 635 (M⁺) 533 —OCH₃ —H —H —H —H free MS 635 (M⁺) 534 —H —OCH₃ —H —OCH₃ —H free MS 665 (M⁺) 535 —H —CH₃ —H —H —H free MS 619 (M⁺) 536 —CH₃ —H —H —H —H free MS 619 (M⁺) 537 —H —CH₃ —CH₃ —H —H free MS 633 (M⁺) 538 —H —H —F —H —H free MS 623 (M⁺) 539 —H —F —H —H —H free MS 623 (M⁺) 540 —F —H —H —H —H free MS 623 (M⁺) 541 —F —H —F —H —H free MS 641 (M⁺) 542 —F —H —H —H —F free MS 641 (M⁺) 543 —H —H —NO₂ —H —H free MS 650 (M⁺) 544 —H —NO₂ —H —H —H free MS 650 (M⁺) 545 —NO₂ —H —H —H —H free MS 650 (M⁺) 546 —H —CF₃ —H —H —H free MS 673 (M⁺) 547 —H —H —CN —H —H free MS 630 (M⁺) 548 —H —OCF₃ —H —H —H free MS 689 (M⁺) 549 —H —H —COOCH₃ —H —H free MS 664 (M⁺ + 1) 550 —H —H —C(CH₃)₃ —H —H free MS 661 (M⁺) 551 —H —H —OCH₂Ph —H —H free MS 710 (M⁺ − 1) 552 —H —H —Ph —H —H free MS 681 (M⁺) 553 —Cl —H —H —H —Cl free MS 675 (M⁺ + 2) 554 —F —H —H —F —H free MS 641 (M⁺) 555 —H —F —H —F —H free MS 641 (M⁺) 556 —H —H —CF₃ —H —H free MS 674 (M⁺ + 1) 557 —H —H —OCF₃ —H —H free MS 689 (M⁺) 558 —OCF₃ —H —H —H —H free MS 689 (M⁺) 559 —H —COOCH₃ —H —H —H free MS 663 (M⁺) 560 —H —H —C₂H₅ —H —H free MS 633 (M⁺) 561 —H —H —CH(CH₃)₂ —H —H free MS 647 (M⁺) 562 —H —Cl —OCH₃ —H —H free MS 669 (M⁺)

TABLE 184

Example mp (° C.) or No. R₆₀₈ R₆₀₉ R₆₁₀ Form ¹H NMR (solvent) δ ppm 563 —H —CH₃ piperonyl free mp 147-149 564 —H —H piperonyl free mp 138-140 565 —H —CH₃ benzyl free mp 150-152 566 —H —H benzyl free ¹H NMR (CDCl₃) 2.34-2.42 (4H, m), 2.58-2.64 (2H, m), 2.91- 2.96 (2H, m), 3.40-3.43 (2H, m), 3.51 (2H, s), 3.60-3.64 (2H, m), 6.93 (1H, d, J = 8.9 Hz), 7.01- 7.04 (2H, m), 7.20 (2H, d, J = 8.6 Hz), 7.27-7.33 (5H, m), 7.56 (1H, d, J = 8.3 Hz), 7.71-7.75 (1H, m), 8.00 (1H, d, J = 2.0 Hz), 8.16-8.27 (3H, m). 567 —OCH₃ —H piperonyl free mp 142.0-144.5 568 —F —H piperonyl free mp 156.5-157.5 569 —H —H —COOC(CH₃)₃ free ¹H NMR (CDCl₃) 1.46 (9H, s), 2.62-2.67 (2H, m), 2.96-3.01 (2H, m), 3.33-3.39 (6H, m), 3.57- 3.60 (2H, m), 6.94-6.97 (1H, m), 7.05 (2H, d, J = 8.4 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.57 (1H, d, J = 8.1 Hz), 7.71-7.75 (1H, m), 8.00 (1H, d, J = 2.2 Hz), 8.13 (1H, brs), 8.21-8.24 (2H, m). 570 —OC₂H₅ —H piperonyl oxalate ¹H NMR (DMSO-d₆) 1.06 (3H, t, J = 6.9 Hz), 2.39-2.86 (8H, m), 3.40-3.60 (4H, m), 3.65 (2H, s), 3.70-5.20 (4H, m), 6.00 (2H, s), 6.76-6.84 (2H, m), 6.85-7.02 (5H, m), 7.82 (1H, d, J = 8.4 Hz), 7.92 (1H, m), 8.03 (1H, m), 8.20 (1H, d, J = 2.0 Hz), 8.35 (1H, d, J = 2.5 Hz), 10.47 (1H, s).

TABLE 185

Example mp (° C.) or No. R₆₁₁ R₆₁₂ R₆₁₃ Form ¹H NMR (CDCl₃) δ ppm 571 —H —CH₃ piperonyl hydro- mp 218-220 chloride 572 —H —CH₃ benzyl free mp 142-144 573 —OCH₃ —H benzyl free ¹H NMR 2.34-2.40 (4H, m), 2.58- 2.63 (2H, m), 2.89-2.94 (2H, m), 3.39-3.42 (2H, m), 3.50 (2H, s), 3.58-3.61 (2H, m), 3.70 (3H, s), 6.75-6.80 (2H, m), 6.91 (1H, d, J = 8.7 Hz), 7.00 (1H, d, J = 7.9 Hz), 7.24-7.35 (5H, m), 7.69 (2H, d, J = 8.1 Hz), 7.98 (2H, d, J = 8.1 Hz), 8.14-8.18 (1H, m), 8.23 (1H, d, J = 2.3 Hz), 8.59 (1H, s). 574 —OCH₃ —H piperonyl free ¹H NMR 2.31-2.37 (4H, m), 2.57- 2.63 (2H, m), 2.88-2.94 (2H, m), 3.37-3.41 (4H, m), 3.57-3.60 (2H, m), 3.70 (3H, s), 5.93 (2H, s), 6.69- 6.80 (4H, m), 6.84 (1H, brs), 6.90 (1H, d, J = 8.9 Hz), 7.00 (1H, d, J = 7.9 Hz), 7.69 (2H, d, J = 8.1 Hz), 7.98 (2H, d, J = 8.1 Hz), 8.14-8.19 (1H, m), 8.24 (1H, d, J = 2.5 Hz), 8.67 (1H, s). 575 —F —H piperonyl free mp 170.5-171.0 576 —H —H —COOC(CH₃)₃ free ¹H NMR 1.46 (9H, s), 2.66 (2H, t, J = 6.5 Hz), 2.97 (2H, t, J = 6.5 Hz), 3.25-3.48 (6H, m), 3.51-3.65 (2H, m), 6.95 (1H, d, J = 9.7 Hz), 7.04 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.75 (2H, d, J = 8.2 Hz), 8.01 (2H, d, J = 8.2 Hz), 8.18-8.33 (3H, m). 577 —OC₂H₅ —H piperonyl hydro- mp 147.5-149.0 chloride

TABLE 186

Example mp (° C.) No. R₆₁₄ R₆₁₅ R₆₁₆ Xb₇ Form or ¹H NMR 578 —Cl —Cl morpholino —O— free ¹H NMR (CDCl₃) δ 2.60-2.66 (2H, m), 2.96- 3.02 (2H, m), 3.37- 3.41 (2H, m), 3.55- 3.64 (6H, m), 6.96 (1H, d, J = 8.4 Hz), 7.06 (2H, d, J = 8.6 Hz), 7.23- 7.26 (2H, m), 7.58 (1H, d, J = 8.4 Hz), 7.70- 7.74 (1H, m), 7.86 (1H, brs), 7.99 (1H, d, J = 1.9 Hz), 8.19-8.25 (2H, m). 579 —Cl —Cl

—NH— free mp 141-142 580 —Cl —Cl

—S— free mp 169-170 581 —Cl —Cl

—SO₂— free mp 154-156 582 —CF₃ —H

—N(CH₃)— free mp 175-176 583 —Cl —Cl

—N(CH₂Ph)— free mp 171-173 584 —Cl —Cl

—N(CH₂Ph)— free mp 144-146 585 —Cl —Cl

—CO— free mp 129-132 586 —Cl —Cl

—O— free mp 208-210 587 —Cl —Cl —NH(CH₂)₂OPh —O— free mp 129-132 588 —Cl —Cl

—SO— oxalate mp 128-130

TABLE 187

Example No. R₆₁₇ R₆₁₈ Xb₈ R₆₁₉ ¹H NMR (CDCl₃) δ ppm 589 —Cl —Cl —CH═CH— piperonyl 2.33-2.42 (4H, m), 2.62-2.68 (2H, m), (trans) 2.96-3.01 (2H, m), 3.40-3.44 (4H, m), 3.62-3.66 (2H, m), 3.76 (3H, s), 5.95 (2H, s), 6.71-6.77 (2H, m), 6.82-7.07 (7H, m), 7.28-7.32 (1H, m), 7.38-7.46 (1H, m), 7.57 (1H, d, J = 2.0 Hz), 7.83-7.87 (1H, m), 8.19 (1H, d, J = 2.3 Hz). 590 —CF₃ —H —CH═CH— piperonyl 2.33-2.42 (4H, m), 2.62-2.68 (2H, m), (trans) 2.96-3.02 (2H, m), 3.40-3.43 (4H, m), 3.63-3.66 (2H, m), 3.76 (3H, s), 5.94 (2H, s), 6.71-6.79 (2H, m), 6.82-6.89 (3H, m), 6.95 (1H, d, J = 8.7 Hz), 7.00 (1H, d, J = 16.5 Hz), 7.05-7.14 (2H, m), 7.55-7.62 (4H, m), 7.86-7.90 (1H, m), 8.22 (1H, d, J = 2.3 Hz). 591 —CF₃ —H —CO— benzyl 2.38-2.43 (4H, m), 2.63-2.68 (2H, m), 2.97-3.02 (2H, m), 3.43 (2H, brs), 3.51 (2H, s), 3.65 (2H, brs), 3.76 (3H, s), 6.84-6.89 (2H, m), 7.04-7.09 (2H, m), 7.27-7.31 (5H, m), 7.73-7.88 (4H, m), 8.19-8.22 (1H, m), 8.55 (1H, brs). 592 —CF₃ —H —CO— piperonyl 2.35-2.39 (4H, m), 2.62-2.68 (2H, m), 2.96-3.02 (2H, m), 3.41-3.44 (4H, m), 3.62-3.65 (2H, m), 3.76 (3H, s), 5.95 (2H, s), 6.74-6.89 (5H, m), 7.04-7.09 (2H, m), 7.73-7.88 (4H, m), 8.19-8.22 (1H, m), 8.55 (1H, brs). 593 —CF₃ —H —CO— 3-pyridyl 2.69-2.75 (2H, m), 3.01-3.06 (2H, m), 3.14-3.20 (4H, m), 3.59-3.62 (2H, m), 3.77 (3H, s), 3.80-3.84 (2H, m), 6.86-6.92 (2H, m), 7.04-7.11 (2H, m), 7.18-7.20 (2H, m), 7.75 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.1 Hz), 8.15 (1H, t, J = 3.0 Hz), 8.20 (1H, dd, J = 8.7 Hz, 2.3 Hz), 8.30 (1H, t, J = 1.8 Hz), 8.53 (1H, d, J = 2.3 Hz).

TABLE 188

Example No. R₆₂₀ R₆₂₁ M ¹H NMR (solvent ) δ ppm 594 3,4-Cl₂PhNHCON(C₂H₅)— 4-pyridyl-methyl 2 (CDCl₃) 1.16 (3H, t, J = 7.1 Hz), 2.35- 2.45 (4H, m), 2.62-2.67 (2H, m), 2.97- 3.03 (2H, m), 3.42-3.46 (2H, m), 3.51 (2H, s), 3.64-3.68 (2H, m), 3.73 (2H, q, J = 7.1 Hz), 6.07 (1H, d, J = 5.0 Hz), 7.04 (1H, d, J = 8.7 Hz), 7.09-7.14 (3H, m), 7.25-7.30 (5H, m), 7.52 (1H, d, J = 2.6 Hz), 7.61 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.11 (1H, d, J = 2.6 Hz), 8.54 (2H, d, J = 5.9 Hz). 595 4-CF₃PhNHCON(C₂H₅)— piperonyl 2 (CDCl₃) 1.18 (3H, t, J = 7.1 Hz), 2.32- 2.41 (4H, m), 2.61-2.67 (2H, m), 2.97- 3.03 (2H, m), 3.39-3.43 (4H, m), 3.61- 3.65 (2H, m), 3.75 (2H, q, J = 7.1 Hz), 5.94 (2H, s), 6.15 (1H, brs), 6.72- 6.76 (2H, m), 6.83 (1H, d, J = 0.7 Hz), 7.05 (1H, dd, J = 8.7 Hz, 0.5 Hz), 7.11 (2H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.40 (2H, d, J = 8.6 Hz), 7.49 (2H, d, J = 8.7 Hz), 7.63 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8. 14 (1H, dd, J = 2.8 Hz, 0.5 Hz). 596 4-CF₃PhNHCON(C₂H₅)— 4-pyridyl-methyl 2 (CDCl₃) 1.18 (3H, t, J = 7.1 Hz), 2.35- 2.45 (4H, m), 2.62-2.68 (2H, m), 2.98- 3.03 (2H, m), 3.42-3.46 (2H, m), 3.51 (2H, s), 3.66 (2H, t, J = 5.0 Hz), 3.75 (2H, q, J = 7.1 Hz), 6.18 (1H, brs), 7.05 (1H, dd, J = 8.7 Hz, 0.5 Hz), 7.11 (2H, d, J = 8.4 Hz), 7.25-7.31 (4H, m), 7.40 (2H, d, J = 8.7 Hz), 7.49 (2H, d, J = 8.7 Hz), 7.63 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.13 (1H, dd, J = 2.6 Hz, 0.5 Hz), 8.53-8.55 (2H, m). 597 4-CF₃PhNHCON(C₂H₅)— 2-pyridyl 2 (CDCl₃) 1.17 (3H, t, J = 7.1 Hz), 2.68- 2.74 (2H, m), 3.02-3.07 (2H, m), 3.46- 3.53 (6H, m), 3.70-3.78 (4H, m), 6.12 (1H, brs), 6.62-6.67 (2H, m), 7.04 (1H, d, J = 8.7 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.31 (2H, d, J = 8.6 Hz), 7.40 (2H, d, J = 8.7 Hz). 7.45-7.52 (3H, m), 7.60 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.07 (1H, d, J = 2.5 Hz), 8.16-8.19 (1H, m).

TABLE 189

Example No. R₆₂₂ R₆₂₃ R₆₂₄ R₆₂₅ mp (° C.) or ¹H NMR (CDCl₃) δ ppm 598 —Cl —Cl —H

mp 169-171 599 —Cl —Cl —H

mp 158-160 600 —Cl —Cl —H

mp 183-186 601 —CF₃ —H —F

¹H NMR 3.00 (3H, s), 3.20- 3.36 (2H, m), 3.57-3.80 (2H, m), 4.07 (2H, s), 4.14-4.34 (2H, m), 4.51 (2H, s), 5.94 (2H, s), 6.32- 6.50 (2H, m), 6.65-6.80 (3H, m), 6.92 (1H, d, J = 9.4 Hz), 7.02 (1H, t, J = 8.8 Hz), 7.71 (2H, d, J = 8.1 Hz), 7.98 (2H, d, J = 8.1 Hz), 8.10-8.20 (1H, m), 8.18 (1H, s), 8.30 (1H, s). 602 —CF₃ —H —H

¹H NMR 1.45 (6H, s), 2.14 (2H, brs), 2.33 (2H, brs), 2.87 (3H, s), 3.32 (2H, s), 3.63 (2H, brs), 3.92 (2H, brs), 5.93 (2H, s), 6.68- 6.75 (2H, m), 6.82 (1H, d, J = 1.0 Hz), 6.92 (2H, d, J = 9.2 Hz), 6.93 (1H, d, J = 9.1 Hz), 7.00 (2H, d, J = 9.2 Hz), 7.77 (2H, d, J = 8.1 Hz), 7.81 (1H, s), 8.00 (2H, d, J = 8.1 Hz), 8.19 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.26 (1H, d, J = 2.1 Hz). 603 —CF₃ —H —OCH₃

¹H NMR 1.33-1.45 (2H, m), 1.82-1.96 (3H, m), 2.28 (2H, d, J = 6.8 Hz), 2.39-2.41 (4H, m), 2.72 (2H, t, J = 10.1 Hz), 3.43 (2H, s), 3.48 (2H, brs), 3.57- 3.62 (4H, m), 3.72 (3H, s), 5.95 (2H, s), 6.48 (1H, dd, J = 8.7 Hz, 2.5 Hz), 6.56 (1H, d, J = 2.5 Hz), 6.71-6.77 (2H, m), 6.86 (2H, d, J = 8.6 Hz), 6.97 (1H, d, J = 8.6 Hz), 7.70 (2H, d, J = 8.4 Hz), 8.00 (2H, d, J = 8.1 Hz), 8.13 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.22 (1H, d, J = 2.5 Hz), 8.40 (1H, s).

TABLE 190

Example mp (° C.) or No. R₆₂₆ R₆₂₇ R₆₂₈ R₆₂₉ ¹H NMR (DMSO-d₆) δ ppm 604 —CF₃ —H —CH₃ —OC₂H₅ ¹H NMR 1.03 (3H, t, J = 6.9 Hz), 2.52-2.68 (6H, m), 2.69-2.82 (2H, m), 3.39-3.61 (4H, m), 3.72 (2H, s), 3.89 (2H, q, J = 6.9 Hz), 4.00-5.90 (4H, m), 6.01 (2H, s), 6.74 (1H, dd, J = 8.0 Hz, 1.8 Hz), 6.76 (1H, d, J = 8.9 Hz), 6.82 (1H, dd, J = 8.0 Hz, 1.3 Hz), 6.84- 6.97 (4H, m), 7.26 (1H, dd, J = 9.0 Hz, 3.1 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J = 3.1 Hz), 7.65 (2H, d, J = 8.0 Hz). 605 —CF₃ —H —C₂H₅ —OC₂H₅ ¹H NMR 1.02 (3H, t, J = 6.9 Hz), 1.08 (3H, t, J = 6.9 Hz), 2.53-2.84 (8H, m), 3.43 (2H, q, J = 6.9 Hz), 3.46-3.62 (4H, m), 3.72 (2H, s), 3.88 (2H, q, J = 6.9 Hz), 4.30-5.90 (4H, m), 6.01 (2H, s), 6.69- 6.78 (2H, m), 6.82 (1H, dd, J = 8.0 Hz, 1.4 Hz), 6.83- 6.97 (4H, m), 7.19 (1H, dd, J = 9.0 Hz, 3.1 Hz), 7.37- 7.48 (3H, m), 7.65 (2H, d, J = 8.1 Hz). 606 —Cl —Cl —CH₃ —H ¹H NMR 2.48-2.67 (6H, m), 2.68-2.82 (2H, m), 2.98 (3H, s), 3.37-3.62 (4H, m), 3.70 (2H, s), 4.50- 5.90 (4H, m), 6.01 (2H, s), 6.78-6.95 (6H, m), 7.13- 7.23 (3H, m), 7.28 (1H, dd, J = 9.0 Hz, 3.3 Hz), 7.48 (1H, d, J = 2.0 Hz), 7.57 (1H, d, J = 8.3 Hz), 7.61 (1H, d, J = 3.1 Hz). 607 —Cl —Cl —C₂H₅ —H ¹H NMR 1.09 (3H, t, J = 6.9 Hz), 2.48-2.66 (6H, m), 2.69-2.82 (2H, m), 3.35-3.59 (6H, m), 3.67 (2H, s), 4.00-5.90 (4H, m), 6.00 (2H, s), 6.76-6.94 (6H, m), 7.13-7.25 (4H, m), 7.47 (1H, d, J = 1.9 Hz), 7.52- 7.61 (2H, m). 608 —CF₃ —H —CH₃ —F ¹H NMR 2.50-2.72 (6H, m), 2.72-2.88 (2H, m), 2.98 (3H, s), 3.32-3.61 (4H, m), 3.70 (2H, brs), 4.67 (2H, s), 6.00 (2H, s), 6.80 (1H, dd, J = 7.9 Hz, 1.4 Hz), 6.85-6.95 (3H, m), 6.98-7.11 (2H, m), 7.11-7.22 (1H, m), 7.29 (1H, dd, J = 9.0 Hz, 3.1 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J = 3.1 Hz), 7.66 (2H, d, J = 8.0 Hz). 609 —Cl —Cl —C₂H₅ —F ¹H NMR 1.00-1.20 (3H, m), 2.46-2.72 (6H, m), 2.72-2.89 (2H, m), 3.29-3.61 (6H, m), 3.71 (2H, brs), 4.46 (2H, s), 6.01 (2H, s), 6.81 (1H, dd, J = 8.0 Hz, 1.4 Hz), 6.85-6.95 (3H, m), 6.98-7.11 (2H, m), 7.13- 7.28 (3H, m), 7.45 (1H, d, J = 3.1 Hz), 7.46 (1H, d, J = 1.9 Hz), 7.56 (1H, d, J = 8.3 Hz). 610 —Cl —Cl —CH₃ —OC₂H₅ ¹H NMR 1.02 (3H, t, J = 6.9 Hz), 2.42-2.81 (8H, m), 2.94 (3H, s), 3.00-4.30 (10H, m), 4.49 (2H, s), 6.00 (2H, s), 6.71-6.83 (3H, m), 6.84-6.95 (4H, m), 7.18 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.26 (1H, dd, J = 9.0 Hz, 3.2 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.50 (1H, d, J = 3.0 Hz), 7.55 (1H, d, J = 8.3 Hz). 611 —Cl —Cl —C₂H₅ —OC₂H₅ ¹H NMR 1.01 (3H, t, J = 7.0 Hz), 1.06 (3H, t, J = 7.0 Hz), 2.40-2.83 (8H, m), 2.90-4.50 (14H, m), 6.00 (2H, s), 6.70-6.82 (3H, m), 6.84-6.95 (4H, m), 7.15-7.24 (2H, m), 7.39-7.48 (2H, m), 7.55 (1H, d, J = 8.3 Hz). 612 —Cl —Cl —C₂H₅ —OCH₃ mp 91.0-96.5 dec 613 —CF₃ —H —C₂H₅ —F mp 104-107

TABLE 191

Example No. R₆₃₀ R₆₃₁ Form ¹H NMR (solvent) δ ppm 614 —H piperonyl free (CDCl₃) 2.30-2.34 (2H, m), 2.36-2.40 (2H, m), 2.56-2.62 (2H, m), 2.91-2.96 (2H, m), 3.01 (3H, s), 3.37-3.40 (4H, m), 3.60- 3.64 (2H, m), 4.50 (2H, s), 5.94 (2H, s), 6.72- 6.73 (2H, m), 6.80 (1H, d, J = 8.9 Hz), 6.84 (1H, brs), 6.98 (2H, d, J = 8.6 Hz), 7.11 (1H, dd, J = 8.9 Hz, 3.3 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 7.9 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.70 (1H, d, J = 3.3 Hz). 615 —H 3-pyridyl free (CDCl₃) 2.63-2.69 (2H, m), 2.95-3.01 (5H, m), 3.08-3.18 (4H, m), 3.54-3.58 (2H, m), 3.78-3.81 (2H, m), 4.50 (2H, s), 6.79 (1H, d, J = 8.9 Hz), 6.99 (2H, d, J = 8.6 Hz), 7.10 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.17- 7.22 (4H, m), 7.34 (2H, d, J = 8.1 Hz), 7.58 (2H, d, J = 7.9 Hz), 7.67 (1H, d, J = 2.8 Hz), 8.12-8.14 (1H, m), 8.29-8.30 (1H, m). 616 —H 4-pyridylmethyl free (CDCl₃) 2.33 (2H, t, J = 5.0 Hz), 2.41 (2H, t, J = 5.1 Hz), 2.57-2.63 (2H, m), 2.92- 2.97 (2H, m), 3.02 (3H, s), 3.41 (2H, t, J = 5.0 Hz), 3.50 (2H, s), 3.65 (2H, t, J = 5.1 Hz), 4.51 (2H, s), 6.80 (1H, d, J = 8.9 Hz), 6.98 (2H, d, J = 8.4 Hz), 7.11 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 5.6 Hz), 7.34 (2H, d, J = 8.3 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.69 (1H, d, J = 3.1 Hz), 8.55 (2H, d, J = 5.8 Hz). 617 —H benzyl hydrochloride (DMSO-d₆) 2.64-2.69 (2H, m), 2.75- 2.81 (2H, m), 2.92-3.02 (5H, m), 3.23- 3.32 (2H, m), 3.41-3.51 (2H, m), 4.02- 4.08 (1H, m), 4.31 (2H, brs), 4.43-4.48 (1H, m), 4.64 (2H, brs), 6.86 (1H, d, J = 9.1 Hz), 6.90 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.29 (1H, dd, J = 9.1 Hz, 3.1 Hz), 7.42-7.47 (5H, m), 7.56-7.57 (2H, m), 7.62 (1H, d, J = 3.1 Hz), 7.69 (2H, d, J = 8.1 Hz), 11.08 (1H, brs). 618 —OCH₃ piperonyl hydrochloride (DMSO-d₆) 2.59-3.09 (6H, m), 2.97 (3H, s), 3.16-3.61 (4H, m), 3.65 (3H, s), 3.97- 4.13 (1H, m), 4.14-4.28 (2H, m), 4.38- 4.51 (1H, m), 4.58 (2H, s), 6.06 (2H, s), 6.72- 6.80 (2H, m), 6.89 (1H, d, J = 8.0 Hz), 6.93- 7.03 (3H, m), 7.18 (1H, s), 7.26 (1H, dd, J = 9.0 Hz, 3.2 Hz), 7.42 (2H, d, J = 8.0 Hz), 7.49 (1H, d, J = 3.1 Hz), 7.67 (2H, d, J = 8.0 Hz), 10.81 (1H, brs).

TABLE 192

Example No. R₆₃₂ R₆₃₃ R₆₃₄ R₆₃₅ Form ¹H NMR (DMSO-d₆) δppm 619 —CF₃ —H —C₂H₅ —H TsOH 1.11(3H, t, J = 6.9 Hz), 2.28(3H, s), salt 2.54-3.02(7H, m), 3.17-3.48(3H, m), 3.47(2H, q, J = 6.9 Hz), 3.97-4.12(1H, m), 4.15-4.31(2H, m), 4.38-4.52 (1H, m), 4.58(2H, s), 6.07(2H, s), 6.78- 7.26(11H, m), 7.39-7.49(4H, m), 7.53(1H, d, J = 3.1 Hz), 7.68(2H, d, J = 8.2 Hz), 9.45-9.69(1H, m). 620 —CF₃ —H —(CH₂)₂OCH₃ —H TsOH 2.27(3H, s), 2.52-3.03(7H, m), salt 3.24(3H, s), 3.17-3.70(10H, m), 3,95- 4.13(1H, m), 4.15-4.32 (2H, m), 4.36- 4.54(1H, m), 4.66(2H, s), 6.07(2H, s), 6.80(1H, d, J = 8.9 Hz), 6.83-7.07(5H, m), 7.10 (2H, d, J = 7.8 Hz), 7.13- 7.26(3H, m), 7.37-7.49 (4H, m), 7.52(1H, d, J = 3.1 Hz), 7.67(2H, d, J = 8.1 Hz), 9.46-9.69(1H, m). 621 —Cl —Cl —CH₃ —OCH₃ hydro- 2.60-3.15(7H, m), 2.94(3H, s), 3.15- chloride 3.38(2H, m), 3.38-3.60(1H, m), 3.65(3H, s), 4.07(1H, d, J = 15.7 Hz), 4.20(2H, brs), 4.38-4.60(1H, m), 4.48 (2H, s), 6.06(2H, s), 6.73-6.81(2H, m), 6.90(1H, d, J = 8.0 Hz), 6.93-7.05(3H, m), 7.16-7.24(2H, m), 7.29(1H, dd, J = 8.9 Hz, 3.2 Hz), 7.47(1H, d, J = 1.9 Hz), 7.50(1H, d, J = 3.1 Hz), 7.56(1H, d, J = 8.2 Hz), 11.10(1H, brs). 622 —Cl —Cl —CH₃ —F hydro- 2.58-3.17(7H, m), 2.96(3H, s), 3.18- chloride 3.38(2H, m), 3.38-3.70(1H, m), 4.00- 4.18(1H, m), 4.20(2H, brs), 4.33- 4.60(1H, m), 4.50(2H, s), 6.06(2H, s), 6.92(1H,d, J = 9.0 Hz), 6.95-7.14(4H, m), 7.16-7.25(3H, m), 7.31(1H, dd, J = 9.0 Hz, 3.1 Hz), 7.47(1H, d, J = 1.9 Hz), 7.51(1H, d, J = 3.1 Hz), 7.56(1H, d, J = 8.2 Hz), 11.10(1H, brs). 623 —CF₃ —H —C₂H₅ —OCH₃ hydro- 1.09(3H, t, J = 6.9 Hz), 2.58-3.11(8H, chloride m), 3.15-3.58(4H, m), 3.64(3H, s), 3.94-4.12(1H, m), 4.14-4.28(2H, m), 4.36-4.50(1H, m), 4.54(2H, s), 6.69- 6.79(2H, m), 6.88(1H, d, J = 8.0 Hz), 6.92-7.02(3H, m), 7.12-7.24(2H, m), 7.37-7.49 (3H, m), 7.67(2H, d, J = 8.1 Hz), 10.77(1H, brs). (TsOH means a p-toluenesulfonic acid. Hereinafter TsOH indicates the same meaning.)

TABLE 193

Example No. R₆₃₆ R₆₃₇ R₆₃₈ R₆₃₉ R₆₄₀ R₆₄₁ Form mp (° C.) or ¹H NMR 624 Y_(a2) —H —H Y_(a1) —H —H hydrochloride ¹H NMR (DMSO-d₆) δ 2.56- 2.72(2H, m), 2.73-2.94(3H, m), 2.96-3.10(1H, m), 3.12- 3.52(4H, m), 3.91-4.07(1H, m), 4.10-4.26(2H, m), 4.33- 4.48(1H, m), 6.05(2H, s), 6.82(1H, d, J = 8.2 Hz), 6.89-7.02(4H, m), 7.09(1H, t, J = 76 Hz), 7.14-7.25(2H, m), 7.35(1H, d, J = 7.6 Hz), 7.74(2H, d, J = 9.0 Hz), 7.81(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22(1H, d, J = 2.1 Hz), 10.45 (1H, s), 11.15(1H, brs). 625 Y_(a2) —H —H —H Y_(a1) —H oxalate mp 134-143 626 —H —H Y_(a2) —H —H Y_(a1) fumarate mp 123-126 627 —H Y_(a2) —H —H —H Y_(a1) hydrochloride mp 141-153

TABLE 194

Example No. R₆₄₂ MS (M⁺ + H) 628

540 629

574 630 morpholino 528 631

574 632

673 633

513 634

543 635

632 636

555 637

689 638

655 639

626

TABLE 195

Example No. R₆₄₃ R₆₄₄ MS (M⁺ + H) 640 —CH₃ cyclohexyl 554 641 —H cyclohexyl 540 642 —C₂H₅ —Ph 562 643 —CH₃ 4-CH₃Ph— 562 644 —H cycloheptyl 554 645 —H cyclooctyl 569 646 —H benzyl 548 647 —H 2-ClPhCH₂— 584 648 —H 3-ClPhCH₂— 584 649 —H 4-ClPhCH₂— 584 650 —CH₃ Ph(CH₂)₂— 577 651 —CH₃ 3,4-(CH₃O)₂PhCH₂— 623 652 —CH₃ benzyl 562 653 —C₂H₅ benzyl 576 654 —H PhOCH₂CH(CH₃)— 593 655 —C₂H₅ cyclohexyl 569 656 —H —C₂H₅ 486 657 —H —(CH₂)₂CH₃ 500 658 —H —(CH₂)₂OCH₃ 516 659 —C₂H₅ cyclohexylmethyl 583 660 —H 4-CH₃OPhCH₂— 578 661 —H 4-CH₃OPh(CH₂)₂— 593 662 —H 4-CF₃OPhCH₂— 632 663 —H 4-CF₃OPh— 618 664 —H 4-ClPh(CH₂)₂— 598 665 —H piperonyl 592 666 —H —(CH₂)₂OPh 579 667 —H cyclopentyl 527 668 —H cyclohexylmethyl 554 669 —H 4-hydroxycyclohexan-1-yl 556 670 —H 4-FPhCH₂— 566 671 —H —CH(CH₃)Ph 562 672 —H —(CH₂)₃Ph 576 673 —H —Ph 534 674 —H 4-CH₃OPh— 564 675 —H —(CH₂)₂Ph 562 676 —H 3-PhOPh— 627 677 —H 4-PhOPh— 627 678 —H 2-CH₃OPh(CH₂)₂— 593 679 —H 2-FPh(CH₂)₂— 580

TABLE 196

Ex- MS ample (M⁺ + No. R₆₄₅ R₆₄₆ H) 680 —H

632 681 —H —CH(CH₃)₂ 501 682 —CH₃

578 683 —(CH₂)₂OH —(CH₂)₂OH 547 684 —CH₃ —(CH₂)₂N(CH₃)₂ 544 685 —H —(CH₂)₃CH₃ 515 686 —H cyclopropyl 499 687 —H 2-pyridylmethyl 550 688 —H 3-pyridylmethyl 550 689 —H —CH₂CH(CH₃)₂ 515 690 —H cyclopropylmethyl 513 691 —H

567 692 —H

570 693 —H

572

TABLE 197

Example No. R₆₄₇ R₆₄₈ ¹H NMR or MS 694 —H 4-CF₃OPhO— MS 702(M⁺ + H) 695 —H benzyl MS 617(M⁺ + H) 696 —OH 4-ClPh— MS 654(M⁺ + H) 697 —H —H MS 526(M⁺ + H) 698 —H —Ph MS 602(M⁺ + H) 699 —H piperonyl ¹H NMR (CDCl₃) δ 1.11-1.16(5H, m), 1.65-1.71(3H, m), 2.48(2H, d, J = 6.4 Hz), 2.54-2.58(1H, m), 2.95-3.04(1H, m), 3.35(2H, q, J = 7.1 Hz), 3.84-3.89 (1H, m), 4.01(2H, s), 4.52-4.57(1H, m), 5.93(2H, s), 6.56-6.63(4H, m), 6.73(1H, d, J = 7.8 Hz), 6.79(1H, d, J = 8.7 Hz), 6.92(2H, d, J = 9.1 Hz), 7.52 (1H, d, J = 8.4 Hz), 7.72(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.99(1H, d, J = 2.0 Hz), 8.04(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.26(1H, d, J = 2.5 Hz), 8.56(1H, brs). 700 —H

MS 610(M⁺ + H) 701 —H 4-CH₃OPhCONH— MS 676(M⁺ + H) 702 —H —N(CH₃)CH₂Ph MS 646(M⁺ + H) 703 —H 4- MS 690(M⁺ + H) CH₃PhO(CH₂)₂N(CH₃)— 704 —OH —Ph MS 619(M⁺ + H) 705 —H 4-CNPhO— MS 644(M⁺ + H) 706 —H 2-ClPhCH₂— MS 653(M⁺ + H) 707 —CH₂(CH₂)₃CH₂— MS 595(M⁺ + H)

TABLE 198

Example No. R₆₄₉ R₆₅₀ R₆₅₁ R₆₅₂ R₆₅₃ M ¹H NMR (solvent) δppm 708 —Cl —Cl —CH₃ —CONH₂ —H 1 (DMSO-d₆) 1.79-2.02(4H, m), 2.96(3H, s), 3.37-3.67(3H, m), 4.19(2H, s), 6.61- 6.70(2H, m), 6.89-6.95(3H, m), 7.83(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.13(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, d, J = 2.0 Hz), 8.43(1H, d, J = 2.6 Hz), 10.51(1H, s). 709 —Cl —Cl —CH₃ —H benzyl 2 (CDCl₃) 1.18-1.26(2H, m), 1.57(3H, brs), 1.58-1.74(2H, m), 2.49-2.58(2H, m), 3.83(1H, d, J = 13.5 Hz), 4.08 (2H, s), 4.56(1H, d, J = 13.5 Hz), 6.40(1H, d, J = 8.9 Hz), 6.67(2H, d, J = 9.1 Hz), 6.98(2H, d, J = 9.1 Hz), 7.12-7.32 (5H, m), 7.56(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.98(1H, d, J = 2.1 Hz), 8.03-8.10(2H, m), 8.24(1H, d, J = 2.6 Hz). 710 —CF₃ —H —C₂H₅ —H piperonyl 2 (CDCl₃) 1.12.1.17(5H, m), 1.64- 1.71(3H, m), 2.48(2H, d, J = 6.6 Hz), 2.53-2.58(1H, m), 2.94-3.03(1H, m), 3.37(2H, q, J = 7.1 Hz), 3.84-3.89(1H, m), 4.01(2H, s), 4.53.4.58(1H, m), 5.93(2H, s), 6.56-6.63(4H, m), 6.73 (1H, d, J = 7.8 Hz), 6.82(1H, d, J = 8.9 Hz), 6.95(2H, d, J = 9.1 Hz), 7.72 (2H, d, J = 8.3 Hz), 7.99 (2H, d, J = 8.1 Hz), 8.10(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.27(1H, d, J = 2.6 Hz), 8.37(1H, brs). 711 —Cl —Cl —CH₃ —H piperonyl 2 (CDCl₃) 1.03.1.17(2H, m), 1.64-1.74 (3H, m), 2.46-2.57(3H, m), 2.97-3.04 (4H, m), 3.80-3.85(1H, m), 4.07(2H, s), 4.51-4.55(1H, m), 5.92(2H, s), 6.56- 6.63(4H, m), 6.73(1H, d, J = 7.8 Hz), 6.79(1H, d, J = 8.9 Hz), 6.94(2H, d, J = 8.9 Hz), 7.52(1H, d, J = 8.4 Hz), 7.71 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.98(1H, d, J = 2.1 Hz), 8.04(1H, d, J = 8.9 Hz), 8.25(1H, d, J = 2.3 Hz), 8.49(1H, brs). 712 —CF₃ —H —CH₃ —H piperonyl 2 (CDCl₃) 1.09-1.17(2H, m), 1.67- 1.70(3H, m), 2.47-2.52(3H, m), 2.94- 3.03(4H, m), 3.80-3.85(1H, m), 4.06(2H, s), 4.50-4.55(1H, m), 5.92(2H, s), 6.55-6.65(4H, m). 6.73(1H, d, J = 7.9 Hz), 6.81(1H, d, J = 8.9 Hz), 6.95(2H, d, J = 8.9 Hz), 7.70(2H, d, J = 8.1 Hz), 7.99 (2H, d, J = 8.1 Hz), 8.09(1H, dd, J = 8.9 Hz, 2.1 Hz), 8.26(1H, d, J = 2.6 Hz), 8.48(1H, brs).

TABLE 199

Example No. R₆₅₄ R₆₅₅ R₆₅₆ ¹H NMR (solvent) δppm 713 —OCH₃ —CH₃

(CDCl₃) 2.38-2.43(4H, m), 2.95(3H, s), 3.40(2H, s), 3.47-3.58(4H, m), 3.63(3H, s), 4.05(2H, s), 4.24(4H, s), 6.12(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.21(1H, d, J = 2.6 Hz), 6.74-6.87(5H, m), 7.44(1H, d, J = 8.4 Hz), 7.69(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.96(1H, d, J = 2.0 Hz), 8.02 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.19(1H, d, J = 2.6 Hz), 9.00(1H, s). 714 —F —CH₃ 3-furylmethyl (DMSO-d₆) 2.32(2H, brs), 2.41(2H, brs), 2.93(3H, s), 3.37(2H, s), 3.44(4H, brs), 4.29(2H, s), 6.40-6.44(2H, m), 6.56(1H, dd, J = 14.5 Hz, 2.8 Hz), 7.01-7.08(2H, m), 7.58(1H, s), 7.62(1H, s), 7.84(1H, d, J = 8.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.16(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, d, J = 2.0 Hz), 8.39(1H, d, J = 2.6 Hz), 10.53(1H, s). 715 —F —CH₃

(DMSO-d₆) 2.30(2H, brs), 2.39(2H, brs), 2.93(3H, s), 3.38(2H, s), 3.44(4H, brs), 4.22(4H, s), 4.28(2H, s), 6.41(1H, dd, J = 8.6 Hz, 2.2 Hz), 6.56(1H, dd, J = 14.4 Hz, 2.8 Hz), 6.76-6.81(3H, m), 7.01-7.08(2H, m), 7.84 (1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.16(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, d, J = 2.0 Hz), 8.39(1H, d, J = 2.5 Hz), 10.53(1H, s). 716 —H —CH₃ 3-furylmethyl (CDCl₃) 2.42(4H, brs), 2.97(3H, s), 3.40(2H, s), 3.50(2H, brs), 3.61(2H, brs), 4.07(2H, s), 6.38(1H, d, J = 1.5 Hz), 6.63(2H, d, J = 9 1 Hz), 6.80(1H, d, J = 8.9 Hz), 6.95 (2H, d, J = 9.1 Hz), 7.34(1H, s), 7.40(1H, t, J = 1.5 Hz) 7.52(1H, d, J = 8.4 Hz), 7.70(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.97(1H, d, J = 2.0 Hz), 8.04(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz), 8.42(1H, s). 717 —OCH₃ —CH₃ 3-furylmethyl (CDCl₃) 2.40-2.44(4H, m), 2.96(3H, s), 3.39(2H, s), 3.49-3.63(4H, m), 3.63(3H, s), 4.06(2H, s), 6.12(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.22(1H, d, J = 2.5 Hz), 6.38(1H, s) 6.76(1H, d, J = 8.7 Hz), 6.86(1H, d, J = 8.7 Hz), 7.33-7.47(3H, m), 7.69(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.96-8.04(2H, m), 8.20(1H, d. J = 2.3 Hz), 8.92(1H, s).

TABLE 200

Example No. R₆₅₇ R₆₅₈ R₆₅₉ Property 718 —CH₃ —CH₃ 3-furylmethyl mp 116.5-118.0° C. 719 —H —C₂H₅

MS 606(M⁺ + H) 720 —H —C₂H₅

MS 645(M⁺ + H) 721 —H —C₂H₅

¹H NMR (CDCl₃) δ 1.16(3H, t, J = 7.1 Hz), 3.04(4H, brs), 3.40(2H, q, J = 7.1 Hz), 3.66- 3.76(4H, m), 4.07(2H, s), 5.91 (2H, s), 6.36(1H, dd, J = 8.4 Hz, 2.5 Hz), 6.55(1H, d, J = 2.3 Hz), 6.66(2H, d, J = 9.1 Hz), 6.73(1H, d, J = 8.4 Hz), 6.83(1H, d, J = 8.9 Hz), 6.96(2H, d, J = 8.9 Hz), 7.54(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.98(1H, d, J = 2.1 Hz), 8.07(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, brs), 8.24(1H, d, J = 2.5 Hz). 722 —H —CH₃

¹H NMR (CDCl₃) δ 3.00-3.03(7H, m), 3.64(2H, brs), 3.75 (2H, brs), 4.12(2H, s), 5.91(2H, s), 6.36(1H, dd, J = 8.4 Hz, 2.5 Hz), 6.55(1H, d, J = 2.3 Hz), 6.68(2H, d, J = 9.1 Hz), 6.73 (1H, d, J = 8.4 Hz), 6.83(1H, d, J = 8.9 Hz), 6.98(2H, d, J = 9.1 Hz), 7.54(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.98(1H, d, J = 2.1 Hz), 8.07(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, brs), 8.23(1H, d, J = 3.0 Hz). 723 —H —C₂H₅

¹H NMR (DMSO-d₆) δ 1.11(3H, t, J = 7.1 Hz), 2.31(2H, brs), 2.38(2H, brs), 3.22- 3.58(8H, m), 4.16(2H, s), 4.21(4H, s), 6.56(2H, d, J = 9.0 Hz), 6.71-6.85(3H, m), 6.90(2H, d, J = 9.0 Hz), 6.93(1H, d, J = 8.9 Hz), 7.83(1H, d, J = 8.4 Hz), 7.95 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, d, J = 2.0 Hz), 8.43(1H, d, J = 2.6 Hz), 10.51(1H, s). 724 —H —C₂H₅

¹H NMR (CDCl₃) δ 1.13(3H, t, J = 7.0 Hz), 2.10-2.25(2H, m), 2.42(4H, brs), 3.34(2H, q, J = 7.0 Hz), 3.42(2H, s), 3.50 (2H, brs), 3.61(2H, brs), 4.01(2H, s), 4.11-4.31(4H, m), 6.59 (2H, d, J = 9.2 Hz), 6.79(1H, d, J = 8.9 Hz), 6.82-6.98(5H, m), 7.51(1H, d, J = 8.4 Hz), 7.70(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.98 (1H, d, J = 2.8 Hz), 8.03(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.24(1H, d, J = 2.8 Hz), 8.54(1H, s).

TABLE 201

Example No. R₆₆₀ R₆₆₁ R₆₆₂ mp (° C.) or ¹H NMR (solvent) δppm 725 —CH₃ —Ac piperonyl mp 216-217 726 —CH₃ —Ac benzyl ¹H NMR (DMSO-d₆) 1.82(3H, s), 2.09(3H, s), 2.28-2.36 (4H, m), 3.35-3.50(6H, m), 4.44(2H, s), 7.05-7.10(2H, m), 7.20-7.32(7H, m), 7.82(1H, d, J = 8.5 Hz), 7.92(1H, dd, J = 1.9 Hz, 8.5 Hz), 8.15-8.20(2H, m), 8.42(1H, d, J = 2.5 Hz), 10.53(1H, s). 727 —H —C₂H₅ 3-pyridyl ¹H NMR (DMSO-d₆) 1.13(3H, t, J = 7.1 Hz), 3.21(2H, brs), 3.29(2H, brs), 3.37(2H, q, J = 7.1 Hz), 3.51-3.78 (4H, m), 4.26(2H, s), 6.60(2H, d, J = 9.0 Hz), 6.92(2H, d, J = 9.0 Hz), 6.94(1H, d, J = 8.9 Hz), 7.23(1H, dd, J = 8.5 Hz, 4.6 Hz), 7.36(1H, dd, J = 8.5 Hz, 1.6 Hz), 7.83(1H, d, J = 8.5 Hz), 7.94(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.03(1H, d, J = 4.6 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, d, J = 2.0 Hz), 8.34(1H, d, J = 2.8 Hz), 8.43(1H, d J = 2.8 Hz), 10.51(1H, s). 728 —F —C₂H₅ piperonyl mp 149-151 729 —F —CH₃ piperonyl mp 199-201 730 —F —Ac piperonyl mp 233-235 731 —OCH₃ —CH₃ piperonyl ¹H NMR (CDCl₃) 2.41-2.43(4H, m), 3.02(3H, s), 3.42(2H, s), 3.49-3.62(4H, m), 3.72(3H, s), 4.08(2H, s), 5.95(2H, s), 6.21(1H, dd, J = 8.7 Hz. 2.6 Hz), 6.32(1H, d, J = 2.8 Hz), 6.73-6.77(2H, m), 6.84(2H, t, J = 4.5 Hz), 6.95(1H, d, J = 8.7 Hz), 7.54(1H, d, J = 8.4 Hz), 7.70(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.97(2H, d, J = 2.0 Hz), 8.05-8.09(1H, m), 8.19(1H, d, J = 2.5 Hz). 732 —H —CH₃ 3-pyridylmetyl ¹H NMR CDCl₃) 2.40-2.42(4H, m), 2.93(3H, s), 3.44(2H, s), 3.48-3.58(4H, m), 4.06(2H, s), 6.58(2H, d, J = 9.1 Hz), 6.74(1H, d, J = 8.9 Hz), 6.90(2H, d, J = 9.1 Hz), 7.25-7.30(1H, m), 7.43(1H, d, J = 8.4 Hz), 7.66-7.73(2H, m), 7.97(1H, d, J = 2.0 Hz), 8.03(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.5 Hz), 8.47-8.51(2H, m), 9.59(1H s). 733 —H —CH₃

¹H NMR (DMSO-d₆) 2.96(3H, s), 3.07- 3.15(4H, m), 3.59 (4H, brs), 3.83(2H, s), 4.31(2H, s), 6.66(2H, d, J = 9.1 Hz), 6.88- 6.95(5H, m), 7.05-7.13(4H, m), 7.20- 7.24(2H, m), 7.83(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, d, J = 2.0 Hz), 8.43(1H, d, J = 2.5 Hz), 10.50(1H, s).

TABLE 202

Example No. R₆₆₃ R₆₆₄ MS or ¹H NMR 734 —H —CHPh₂ MS 694(M⁺ + H) 735 —H 3-CH₃OPh— MS 634(M⁺ + H) 736 —H 4-CH₃OPh— MS 634(M⁺ + H) 737 —H 3,4-(CH₃)₂Ph— MS 632(M⁺ + H) 738 —H 2,3-Cl₂Ph— MS 673(M⁺ + H) 739 —H 2,4-F₂Ph— MS 640(M⁺ + H) 740 —H 2-CH₃OPh— MS 634(M⁺ + H) 741 —H 3-CF₃Ph— MS 671(M⁺ + H) 742 —H 2-ClPh— MS 639(M⁺ + H) 743 —H 4-CF₃Ph— MS 671(M⁺ + H) 744 —H —Ph MS 604(M⁺ + H) 745 —H 2-pyridylmethyl MS 619(M⁺ + H) 746 —H 2-pyridyl MS 605(M⁺ + H) 747 —H —(CH₂)₃Ph MS 646(M⁺ + H) 748 —H —(CH₂)₄Ph MS 660(M⁺ + H) 749 —H —(CH₂)₂N(CH₃)₂ MS 599(M⁺ + H) 750 —H cyclopentyl MS 596(M⁺ + H) 751 —H

MS 625(M⁺ + H) 752 —H

MS 641(M⁺ + H) 753 —H —CH(CH₃)Ph MS 634(M⁺ + H) 754 —H —(CH₂)₂Ph MS 632(M⁺ + H) 755 —H —CH₂CONHPh MS 661(M⁺ + H) 756 —H —(CH₂)₃N(CH₃)₂ MS 613(M⁺ + H) 757 —H

MS 639(M⁺ + H) 758 —H —CH₃ MS 542(M⁺ + H) 759 —OCH₃ —H ¹H NMR (CDCl₃) 1.26(3H, t, J = 6.9 Hz), 2.70(1H, brs), 2.82-2.87(4H, m), 3.33(2H, q, J = 6.9 Hz), 3.49-3.57(4H, m), 3.62(3H, s), 4.00(2H, s), 6.09(1H, d, J = 8.7 Hz), 6.20(1H, s), 6.73(1H, d, J = 8.7 Hz), 6.83(1H, d, J = 8.6 Hz), 7.42(1H, d, J = 8.3 Hz), 7.70(1H, d, J = 7.4 Hz), 7.97-8.03(2H, m), 8.23(1H, s), 9.26(1H, brs).

TABLE 203

Example No. R₆₆₅ R₆₆₆ Form ¹H NMR (DMSO-d₆) δppm 760 —Ac piperonyl hydro- 1.84(3H, s), 2.83-3.14(2H, m), 3.23-3.32(2H, chloride m), 4.02(1H, d, J = 13.6 Hz), 4.18-4.27(2H, m), 4.40(1H, d, J = 13.6 Hz), 4.50-4.60 (2H, m), 6.07(2H, s), 6.96-7.03(2H, m), 7.10- 7 25(4H, m), 7.43 (2H, d, J = 8.8 Hz), 7.85(1H, d, J = 8.4 Hz), 7.98(1H, dd, J = 2.0 Hz, 8.4 Hz), 8.24(1H, dd, J = 2.6 Hz, 8.9 Hz), 8.26(1H, d, J = 2.0 Hz), 8.54(1H, d, J = 2.6 Hz), 10.69(1H, s), 11.07(1H, brs). 761 —Ac benzyl hydro- 1.84(3H, s), 2.90-3.17(2H, m), 3.23-3.35(2H, chloride m), 4.03(1H, d, J = 14.4 Hz), 4.28-4.43(3H, m), 4.50-4.62(2H, m), 7.13(1H, d, J = 8.8 Hz), 7.17(2H, d, J = 8.8 Hz), 7.40-7.50(5H, m), 7.58-7.62 (2H, m), 7.85(1H, d, J = 8.4 Hz), 8.00(1H, dd, J = 2.0 Hz, 8.4 Hz), 8.20- 8.29(2H, m), 8.54(1H, d, J = 2.6 Hz), 10.70(1H, s), 11.21 (1H, brs). 762 —C₂H₅ 3-furylmethyl trihydro- 1.11(3H, t, J = 7.1 Hz), 2.75-3.30(3H, m), chloride 3.30-3.50(2H, m), 3.40(2H, q, J = 7.1 Hz), 3.51-3.72(1H, m), 3.95-4.15(1H, m), 4.22(2H, s), 4.30-4.62(3H, m), 6.80-6.85(1H, m), 6.89(2H, d, J = 8.9 Hz), 7.00(1H, d, J = 8.9 Hz), 7.01(2H, d, J = 8.9 Hz), 7.70-7.80(1H, m), 7.84(1H, d, J = 8.5 Hz), 7.88(1H, s), 7.99(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.19(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.27 (1H, d, J = 2.0 Hz), 8.50(1H, d, J = 2.7 Hz), 10.69(1H, s). 763 —C₂H₅ 4-pyridylmethyl tetrahydro- 1.11(3H, t, J = 7.0 Hz), 3.00-3.66(6H, m), chloride 3.41(2H, q, J = 7.0 Hz), 3.90(2H, brs), 4.42(2H, brs), 4.63(2H, brs), 6.82(2H, d, J = 8.8 Hz), 6.98(3H, d, J = 8.8 Hz), 7.84(1H, d, J = 8.4 Hz), 7.98(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.17(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22- 8.39(3H, m), 8.49(1H, d, J = 2.5 Hz), 8.99(2H, d, J = 6.2 Hz), 10.67(1H, s). 764 —CH₃

dihydro- chloride 2.94(3H, s), 2 80-3.22(3H, m), 3.22-3.70(3H, m), 3.95-4.60(6H, m), 6.68(2H, d, J = 9.1 Hz), 6.92(2H, d, J = 9.1 Hz), 6.95(1H, d, J = 8.9 Hz), 7.79(1H, dd, J = 8.4 Hz, 1.6 Hz), 7.84(1H, d, J = 8.4 Hz), 7.96(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.14(1H, dd, J = 8.9 Hz, 2.3 Hz), 8.20(1H, d, J = 8.4 Hz), 8.24(1H, d, J = 2.0 Hz), 8.40(1H, d, J = 1.6 Hz), 8.44(1H, d, J = 2.3 Hz), 9.51(1H, s), 10.57(1H, s).

TABLE 204

Example No. R₆₆₇ R₆₆₈ R₆₆₉ R₆₇₀ R₆₇₁ mp (° C.) or ¹H NMR (solvent) δppm 765 —Cl —Cl —H —CH₃ piperonyl mp 198-200 766 —Cl —Cl —H —C₂H₅ benzyl ¹H NMR (DMSO-d₆) 1.12(3H, t, J = 7.1 Hz), 2.98(4H, brs), 3.34(2H, q, J = 7.1 Hz), 3.20-3.50(2H, m), 3.67(2H, brs), 4.10(2H, brs), 4.23(2H, s), 6.11(2H, s), 6.59(2H, d, J = 9.2 Hz), 6.91(2H, d, J = 9.2 Hz), 6.94(1H, d, J = 8.9 Hz), 7.45(5H, s), 7.84(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.6 Hz), 8.12 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, d, J = 2.0 Hz), 8.43(1H, d, J = 2.6 Hz), 10.51(1H, s). 767 —Cl —Cl —H —CH₃

¹H NMR (DMSO-d₆) 2.94(3H, s), 3.05(4H, brs), 3.40(2H, brs), 3.63(2H, brs), 4.04(2H, brs), 4.26(4H, s), 4.31(2H, brs), 6.09(2H, s), 6.65(2H, d, J = 9.1 Hz), 6.82- 7.06(6H, m), 7.84(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.12(1H, dd, J = 8.8 Hz, 2.5 Hz), 8.22(1H, d, J = 2.0 Hz), 8.43(1H, d, J = 2.5 Hz), 10.51(1H, s). 768 —Cl —Cl —OCH₃ —C₂H₅ piperonyl mp 172-177 769 —CF₃ —H —H —C₂H₅ benzyl ¹H NMR (CDCl₃ + CD₃OD) 1.13(3H, t, J = 6.9 Hz), 3.08(4H, brs), 3.36(2H, q, J = 6.9 Hz), 3.85(4H, brs), 4.09(2H, s), 4.18(2H, s), 6.31 (2H, 5), 6.73(2H, d, J = 8.9 Hz), 6.87(1H, d, J = 9.2 Hz), 6.98(2H, d, J = 8.9 Hz), 7.40-7.44 (5H, m), 7.73(2H, d, J = 8.4 Hz), 8.07(2H, d, J = 8.3 Hz), 8.27(2H, d, J = 7.4 Hz), 9.63(1H, s). 770 —CF₃ —H —H —CH₃

¹H NMR (DMSO-d₆) 2.94(3H, s), 2.95(4H, brs), 3.33(4H, brs), 4.03(2H, brs), 4.26(4H, s), 4.31(2H, brs), 6.09(2H, s), 6.65(2H, d, J = 9.2 Hz), 6.85-7.03(6H, m), 7.93(2H, d, J = 8.2 Hz), 8.14(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.16(2H, d, J = 8.2 Hz), 8.45(1H, d, J = 2.5 Hz), 10.59(1H, s).

TABLE 205

Example No. R₆₇₂ R₆₇₃ R₆₇₄ mp (° C.) or ¹H NMR (solvent) δppm 771 —H —Ac benzyl mp 161-162 772 —CH₃ —Ac piperonyl ¹H NMR (DMSO-d₆) 1.82(3H, s), 2.10(3H, s), 2.23-2.36(4H, m), 3.33-3.45(6H, m), 4.44(2H, s), 5.96(2H, s), 6.72(1H, d, J = 8.0 Hz), 6.82(1H, d, J = 8.0 Hz), 6.84(1H, s), 7.02- 7.10(2H, m), 7.23(1H, d, J = 8.6 Hz), 7.33(1H, s), 7.91(2H, d, J = 8.4 Hz), 8.14(2H, d, J = 8.4 Hz), 8.20(1H, d, J = 8.6 Hz), 8.45 (1H, s), 10.60(1H, s). 773 —CH₃ —Ac benzyl ¹H NMR (DMSO-d₆) 1.82(3H, s), 2.10(3H, s), 2.30-2.37(4H, m), 3.35-3.45(4H, m), 3.47(2H, s), 4.44(2H, s), 7.03-7.10 (2H, m), 7.20- 7.35(7H, m), 7.91(2H, d, J = 8.4 Hz), 8.14(2H, d, J = 8.4 Hz), 8.21(1H, dd, J = 2.5 Hz, 8.9 Hz), 8.45(1H, d, J = 2.5 Hz), 10.60(1H, s). 774 —H —C₂H₅ piperonyl mp 178-180 775 —F —C₂H₅ piperonyl mp 170-172 776 —F —CH₃ piperonyl mp 220-221 777 —OCH₃ —CH₃ piperonyl ¹H NMR (CDCl₃) 2.38-2.42(4H, m), 2.96(3H, s), 3,41(2H, s), 3,47-3.58(4H, m), 3.64(3H, s), 4.05(2H, s), 5.94(2H, s), 6.13 (1H, dd, J = 8.9 Hz, 2.8 Hz), 6.24(1H, d, J = 2.8 Hz), 6.70- 6.89(5H, m), 7.64(2H, d, J = 8.3 Hz), 7.96(2H, d, J = 8.1 Hz), 8.06(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.20(1H, d, J = 2.6 Hz), 8.93(1H, s). 778 —OCH₃ —CH₃

¹H NMR (CDCl₃) 2.38-2.42(4H, m), 2.96(3H, s), 3.40(2H, s), 3.47-3.57(4H, m), 3.98(3H, s), 4.05(2H, s), 4.24(4H, s), 6.13 (1H, dd, J = 8.9 Hz, 2.8 Hz), 6.23(1H, d, J = 2.6 Hz), 6.73- 6.88(5H, m), 7.63(2H, d, J = 8.3 Hz), 7.97(2H, d, J = 8.1 Hz), 8.07(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.20(1H, d, J = 2.5 Hz), 9.11(1H, s). 779 —F —CH₃

¹H NMR (DMSO-d₆) 2.30(2H, brs), 2.39(2H, brs), 2.93(3H, s), 3.38(2H, s), 3.44(4H, brs), 4.22(4H, s), 4.28(2H, s), 6.40-6.43(1H, m), 6.56(1H, dd, J = 14.2 Hz, 2.6 Hz), 6.73- 6.81(3H, m), 7.02-7.08(2H, m), 7.93(2H, d, J = 8.6 Hz), 8.14-8.21(3H, m), 8.49(1H, d, J = 2.6 Hz), 10.61(1H, s). 780 —F —CH₃ 3-furylmethyl ¹H NMR (DMSO-d₆) 2.32(2H, s), 2.41(2H, s), 2.93(3H, s), 3.37(2H, s), 3.44(4H, brs), 4.29(2H, s), 6.40-6.44(2H, m), 6.55(1H, dd, J = 14.5 Hz, 2.8 Hz), 7.02-7.08(2H, m), 7.58- 7.62(2H, m), 7.93(2H, d, J = 8.4 Hz), 8.14- 8.21(3H, m), 8.41(1H, d, J = 2.6 Hz), 10.61(1H, s).

TABLE 206

Example No. R₆₇₅ R₆₇₆ R₆₇₇ mp (° C.) or ¹H NMR (solvent) δppm 781 —OCH₃ —C₂H₅

¹H NMR (CDCl₃) 1.16(3H, t, J = 6.9 Hz), 2.38- 2.43(4H, m), 3.33-3.62(8H, m), 3.66(3H, s), 4.02(2H, s), 4.26(4H, s), 6.14 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.25(1H, d, J = 2.6 Hz), 6.75- 6.90(5H, m), 7.66(2H, d, J = 8.3 Hz), 8.01(2H, d, J = 8.3 Hz), 8.09(1H, dd, J = 9.1 Hz, 2.8 Hz), 8.26(1H, d, J = 2.6 Hz), 9.19(1H, s). 782 —F —Ac piperonyl ¹H NMR (DMSO-d₆) 1.88(3H, s), 2.33(4H, brs), 3.40(2H, s), 3.40(4H, brs), 4.50(2H, s), 5.99(2H, s), 6.73-6.76(1H, m), 6.83-6.86(2H, m), 7.21(1H, d, J = 8.9 Hz), 7.32-7.49(3H, m), 7.94(2H, d, J = 8.3 Hz), 8.16(2H, d, J = 8.1 Hz), 8.25(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.46(1H, d, J = 2.6 Hz), 10.66(1H, s). 783 —H —CH₃ 3-furylmethyl ¹H NMR (CDCl₃) 2.44(4H, brs), 2.99(3H, s), 3.40(2H, s), 3.50 (2H, t, J = 4.9 Hz), 3.62(2H, t, J = 4.9 Hz), 4.07(2H, s), 6.38 (1H, d, J = 1.0 Hz), 6.67(2H, d, J = 9.1 Hz), 6.84(1H, d, J = 8.8 Hz), 6.98(2H, d, J = 9.1 Hz), 7.34(1H, s), 7.40(1H, t, J = 1.6 Hz), 7.73(2H, d, J = 8.2 Hz), 7.99(2H, d, J = 8.2 Hz), 8.11 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.24(1H, s), 8.25(1H, d, J = 2.6 Hz). 784 —OCH₃ —C₂H₅ 3-furylmethyl mp 174-176 785 —OCH₃ —CH₃ 3-furylmethyl mp 160-164 786 —CH₃ —CH₃ —COOC(CH₃)₃ ¹H NMR (CDCl₃) 1.47(9H, s), 2.12(3H, s), 3.01(3H, s), 3.30-3.71(8H, m), 4.09(2H, s), 6.44-6.66(2H m), 6.83(1H d, J = 8.9 Hz), 6.93(1H, d, J = 8.4 Hz), 7.75(2H, d, J = 8.1 Hz), 7.94(1H, s), 7.99(2H, d, J = 8.1 Hz), 8.15(1H, d, J = 9.2 Hz), 8.22(1H, s). 787 —H —C₂H₅

¹H NMR (CDCl₃) 1.18(3H, t, J = 7.1 Hz), 3.03(4H, brs), 3.43 (2H, q, J = 7.1 Hz), 3.67- 3.77(4H, m), 4.08(2H, s), 5.91(2H, s), 6.36(1H, dd, J = 8.4 Hz, 2.3 Hz), 6.55(1H, d, J = 2.5 Hz), 6.68-6.75(3H, m), 6.87(1H, d, J = 8.7 Hz), 7.00(2H, d, J = 8.9 Hz), 7.75(2H, d, J = 8.4 Hz), 7.98(1H, brs), 7.99(2H, d. J = 8.3 Hz), 8.13(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.25(1H, d, J = 2.6 Hz)

TABLE 207

Example No. R₆₇₈ R₆₇₉ R₆₈₀ Form mp (° C.) or ¹H NMR (solvent) δppm 788 —F —(CH₂)₂CH₃ piperonyl free ¹H NMR (CDCl₃) 0.94(3H, t, J = 7.3 Hz), 1.58-1.69(2H, m), 2.45(4H, brs), 3.29(2H, t, J = 7.6 Hz), 3.45(2H, s), 3.49(2H, brs), 3.64(2H, brs), 4.05(2H, s), 5.95(2H, s), 6.34- 6.44(2H, m), 6.75(2H, s), 6.86(1H, s), 6.96(1H, d, J = 8.9 Hz), 7.03(1H, t, J = 9.1 Hz), 7.76(2H, d, J = 8.2 Hz), 7.86(1H, brs), 8.00(2H, d, J = 8.1 Hz), 8.16-8.22(2H, m). 789 —H —CH₃

free ¹H NMR (CDCl₃) 3.02(7H, brs), 3.64(2H, brs), 3.75(2H, brs), 4.12(2H, s), 5.91(2H, s), 6.36(1H, dd, J = 8.4 Hz, 2.5 Hz), 6.55(1H, d, J = 2.5 Hz), 6.70(2H, d, J = 9.1 Hz), 6.73(1H, d, J = 8.3 Hz), 6.85(1H, d, J = 8.9 Hz), 6.99(2H, d, J = 9.2 Hz), 7.73(2H, d, J = 8.3 Hz), 7.98(2H, d, J = 8.3 Hz), 8.12(1H, dd, J = 9.1 Hz, 2.8 Hz), 8.15(1H, brs), 8.24(1H, d, J = 2.5 Hz). 790 —OCH₃ —CH₃ 4-(4-FPhCO)Ph— free ¹H NMR (CDCl₃) 3.03(3H, s), 3.39(4H, brs), 3.70(3H, s), 3.71- 3.79(4H, m), 4.14(2H, s), 6.23 (1H, dd, J = 8.9 Hz, 2.8 Hz), 6.36(1H, d, J = 2.6 Hz), 6.81-6.96(4H, m), 7.09- 7.17(2H, m), 7.68 (2H, d, J = 8.4 Hz), 7.72-7.78(4H, m), 7.99(2H, d, J = 8.3 Hz), 8.09(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.21(1H, d, J = 2.6 Hz), 8.53(1H, s). 791 —OCH₃ —C₂H₅ 4-(4-FPhCO)Ph— free ¹H NMR (CDCl₃) 1.17(3H, t, J = 6.9 Hz), 3.37-3.42(6H, m), 3.67(3H, s), 3.71-3.76(4H, m), 4.08(2H, s), 6.19(1H, dd, J = 8.9 Hz, 2.8 Hz), 6.33(1H, d, J = 2.6 Hz), 6.77- 6.92(4H, m), 7.09-7.15(2H, m), 7.64(2H, d, J = 8.3 Hz), 7.71- 7.77(4H, m), 7.98(2H, d, J = 8.1 Hz), 8.07 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.23(1H, d, J = 2.6 Hz), 8.83(1H, s). 792 —CH₃ —CH₃ 3-furylmethyl hydrochloride mp 158.5-161.0

TABLE 208

Example No. R₆₈₁ R₆₈₂ R₆₈₃ ¹H NMR (DMSO-d₆) δppm 793 —Cl —Cl piperonyl 1.74(3H, s), 2.19-2.34(4H, m), 2.54(2H, t, J = 7.7 Hz), 3.32-3.46(6H, m), 3.76(2H, t, J = 7.7 Hz), 5.96(2H, s), 6.72(1H, d, J = 7.9 Hz), 6.77-6.85(2H, m), 7.11(1H, d, J = 8.8 Hz), 7.17(2H, d, J = 8.6 Hz), 7.31(2H, d, J = 8.6 Hz), 7.83(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.17-8.25(2H, m), 8.51(1H, d, J = 2.4 Hz), 10.57(1H, s). 794 —Cl —Cl benzyl 1.74(3H, s), 2.25-2.37(4H, m), 2.54(2H, t, J = 7.7 Hz), 3.36-3.42(4H, m), 3.46(2H, s), 3.76(2H, t, J = 7.7 Hz), 7.11(1H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.20-7.31(5H, m), 7.34(2H, d, J = 8.6 Hz), 7.83(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.19-8.25(2H, m), 8.51 (1H, d, J = 2.5 Hz), 10.57(1H, s). 795 —CF₃ —H piperonyl 1.74(3H, s), 2.20-2.35(4H, m), 2.54(2H, t, J = 7.7 Hz), 3.34-3.42(6H, m), 3.76(2H, t, J = 7.7 Hz), 5.96(2H, s), 6.72(1H, d, J = 7.8 Hz), 6.78-6.86(2H, m), 7.12(1H, d, J = 8.8 Hz), 7.17(2H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.5 Hz), 7.92(2H, d, J = 8.2 Hz), 8.15(2H, d, J = 8.2 Hz), 8.24(1H, dd, J = 8.8 Hz, 2.5 Hz), 8.54(1H, d, J = 2.5 Hz), 10.65(1H, s). 796 —CF₃ —H benzyl 1.74(3H, s), 2.18-2.36(4H, m), 2.54(2H, t, J = 7.7 Hz), 3.35-3.45(4H, m), 3.46(2H, s), 3.76(2H, t, J = 7.7 Hz), 7.12(1H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.6 Hz), 7.20-7.33(5H, m), 7.34(2H, d, J = 8.6 Hz), 7.92(2H, d, J = 8.3 Hz), 8.15(2H, d, J = 8.3 Hz), 8.24(1H, dd, J = 8.8 Hz, 2.5 Hz), 8.54(1H, d, J = 2.5 Hz), 10.65(1H, s).

TABLE 209

Example No. R₆₈₄ R₆₈₅ R₆₈₆ ¹H NMR (DMSO-d₆) δppm 797 —Cl —Cl benzyl 1.80(3H, s), 3.02(3H, s), 2.70-3.40(5H, m), 3.41- 3.68(1H, m), 3.88-4.10 (1H, m), 4.32(2H, brs), 4.25- 4.50(1H, m), 4.50(2H, d, J = 3.8 Hz), 4.57 (2H, s), 6.94(1H, d, J = 8.9 Hz), 7.02(2H, d, J = 8.7 Hz), 7.22(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.34(1H, dd, J = 8.9 Hz, 3.2 Hz), 7.36(2H, d, J = 8.7 Hz), 7.42-7.49(3H, m), 7.50(1H, d, J = 2.0 Hz), 7.55-7.64(1H, m), 7.62 (2H, d, J = 8.2 Hz), 7.66(1H, d, J = 6.1 Hz). 798 —Cl —Cl piperonyl 1.81(3H, s), 2.75-3.40(5H, m), 3.02(3H, s), 3.43- 3.67(1H, m), 3.90-4.10 (1H, m), 4.22(2H, brs), 4.30- 4.50(1H, m), 4.50(2H, d, J = 4.6 Hz), 4.57 (2H, s), 6.07(2H, s), 6.94(2H, d, J = 8.8 Hz), 6.97-7.07(1H, m), 7.02(2H, d, J = 8.9 Hz), 7.22(1H, dd, J = 8.3 Hz, 1.8 Hz), 7.24(1H, s), 7.34(1H, dd, J = 8.8 Hz, 3.0 Hz), 7.36(2H, d, J = 8.9 Hz), 7.50(1H, d, J = 1.8 Hz), 7.60(1H, d, J = 8.3 Hz), 7.67(1H, d, J = 3.0 Hz). 799 —CF₃ —H benzyl 1.80(3H, s), 3.05(3H, s), 2.70-3.40(5H, m), 3.41- 3.68(1H, m), 3.90-4.08 (1H, m), 4.22-4.45(1H, m), 4.32(2H, brs), 4.50(2H, d, J = 3.5 Hz), 4.67 (2H, s), 6.94(1H, d, J = 8.9 Hz), 7.02(2H, d, J = 8.8 Hz), 7.34(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.36(2H, d, J = 8.8 Hz), 7.39-7.50(5H, m), 7.54-7.64 (2H, m), 7.67(1H, d, J = 3.3 Hz). 7.70(2H, d, J = 8.1 Hz). 800 —CF₃ —H piperonyl 1.80(3H, s), 2.70-3.40(5H, m), 3.05(3H, s), 3.43- 3.65(1H, m), 3.90-4.09 (1H, m), 4.22(2H, s), 4.29- 4.48(1H, m), 4.50(2H, d, J = 4.8 Hz), 4.67(2H, s), 6.07(2H, s), 6.94(1H, d, J = 8.9 Hz), 7.00(2H, d, J = 7.0 Hz), 7.02(2H, d, J = 8.8 Hz), 7.24(1H, d, J = 1.1 Hz), 7.35(1H, dd, J = 8.9 Hz, 2.3 Hz), 7.36(2H, d, J = 8.8 Hz), 7.45(2H, d, J = 8.1 Hz), 7.67(1H, d, J = 3.3 Hz), 7.70(2H, d, J = 8.1 Hz).

TABLE 210

Example No. R₆₈₇ R₆₈₈ R₆₈₉ ¹H NMR (CDCl₃) δppm 801 4-CF₃PhCO— —CH₃ —C₂H₅ 1.19(3H, t, J = 7.1 Hz), 2.11(3H, s), 2.42- 2.45(4H, m), 3.39-3.53(6H, m), 3.63- 3.66(2H, m), 4.04(2H, s), 5.95(2H, s), 6.50-6.54(2H, m), 6.71-6.77(2H, m), 6.85(1H, s), 6.90-6.95(2H, m), 7.75(2H, d, J = 8.2 Hz), 7.87(2H, d, J = 8.1 Hz), 8.17(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.59(1H, d, J = 2.0 Hz). 802 3,4-Cl₂PhNHCO— —OCH₃ —C₂H₅ 1.19(3H, t, J = 7.1 Hz), 2.42(4H, brs), 3.42(2H, q, J = 7.1 Hz), 3.43(2H, s), 3.51(2H, s), 3.62(2H, brs), 3.68(3H, s), 4.04(2H, s), 5.95(2H, s), 6.17(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.28(1H, d, J = 2.6 Hz), 6.73-6.74(2H, m), 6.85(1H, brs), 6.88(1H, d, J = 8.6 Hz), 6.90(1H, d, J = 8.7 Hz), 7.37(1H, d, J = 8.7 Hz), 7.47(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.86(1H, d, J = 2.5 Hz), 8.11(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.31(1H, brs), 8.58(1H, d, J = 2.3 Hz). 803 4-CF₃PhNHCO— —OCH₃ —C₂H₅ 1.19(3H, t, J = 7.1 Hz), 2.42(4H, brs), 3.38-3.47(4H, m), 3.51(2H, brs), 3.62(2H, brs), 3.68(3H, s), 4.05(2H, s), 5.94 (2H, s), 6.17(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.29(1H, d, J = 2.8 Hz), 6.73-6.74(2H, m), 6.84(1H, brs), 6.89(1H, d, J = 8.7 Hz), 6.91(1H, d, J = 8.7 Hz), 7.58(2H, d, J = 8.7 Hz), 7.76(2H, d, J = 8.7 Hz), 8.13(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.44(1H, brs), 8.64(1H, d, J = 2.5 Hz). 804 3,4-Cl₂PhNHCONH— —CONHCH₃ —C₂H₅ 1.07(3H, t, J = 7.0 Hz), 2.30-2.45(4H, m), 2.85(3H, d, J = 4.9 Hz), 3.33(2H, q, J = 7.0 Hz), 3.38(2H, s), 3.38-3.50(2H, m), 3.50-3.65(2H, m), 4.01(2H, s), 5.95(2H, s), 6.55-6.65 (1H, m), 6.69-6.84(5H, m), 7.14(1H, d, J = 3.1 Hz), 7.25-7.35(2H, m), 7.35-7.45(1H, m), 7.65(1H, d, J = 1.5 Hz), 7.72(1H, d, J = 2.6 Hz), 7.84(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.02(1H, s), 8.61(1H, s). 805 4-CF₃PhCH₂— —H —CH₃ 2.42(4H, t, J = 5.1 Hz), 3.02(3H, s), 3.43(2H, s), 3.48(2H, brs), 3.63(2H, brs), 3.95(2H, s), 4.06(2H, s), 5.94(2H, s), 6.70(2H, d, J = 9.0 Hz), 6.73(2H, s), 6.74(1H, d, J = 10.0 Hz), 6.84(1H, s), 7.00(2H, d, J = 9.0 Hz), 7.27(2H, d, J = 8.1 Hz), 7.38(1H, dd, J = 8.4 Hz, 2.5 Hz), 7.54(2H, d, J = 8.1 Hz), 8.03(1H, d, J = 2.5 Hz).

TABLE 211

Example No. R₆₉₀ R₆₉₁ R₆₉₂ R₆₉₃ ¹H NMR (solvent) δppm 806 4-CF₃PhNHCO— —CH₃ —H piperonyl (CDCl₃) 2.17(3H, s), 2.49-2.54(4H, m), 3.45(2H, s), 3.71-3.75(2H, m), 4.26(2H, brs), 5.96(2H, s), 6.75(2H, brs), 6.86(1H, brs), 7.02(1H, d, J = 8.7 Hz), 7.06(1H, d, J = 8.7 Hz), 7.47(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.58(1H, d, J = 2.3 Hz), 7.63(2H, d, J = 8.4 Hz), 7.75(2H, d, J = 8.3 Hz), 7.84(1H, brs), 8.22(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.64(1H, d, J = 2.5 Hz), 9.20(1H, brs). 807 4-CF₃PhOCH₂— —H —H piperonyl (CDCl₃) 2.51-2.54(4H, m), 3.45(2H, s), 3.71-3.75(2H, m), 4.27-4.29(2H, m), 5.05(2H, s), 5.95(2H, s), 6.85(2H, brs), 6.86(1H, brs), 6.96(1H, d, J = 8.4 Hz), 7.02(2H, d, J = 8.6 Hz), 7.14(2H, d, J = 8.9 Hz), 7.56(2H, d, J = 8.6 Hz), 7.64(2H, d, J = 8.9 Hz), 7.78(1H, dd, J = 8.4 Hz, 2.3 Hz), 8.22(1H, d, J = 2.3 Hz), 9.21(1H, brs). 808 4-CF₃PhOCH₂— —H —H 4-pyridylmethyl (CDCl₃) 2.52-2.58(4H, m), 3.55(2H, s), 3.74-3.77(2H, m), 4.29-4.32(2H, m), 5.04(2H, s), 6.96(1H, d, J = 8.4 Hz), 7.02(2H, d, J = 8.4 Hz), 7.15(2H, d, J = 8.9 Hz), 7.26- 7.30(2H, m), 7.56(2H, d, J = 8.6 Hz), 7.64(2H, d, J = 9.1 Hz), 7.78(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.22(1H, d, J = 2.0 Hz), 8.56- 8.58(2H, m), 9.24(1H, brs). 809 4-CF₃PhOCH₂— —CH₃ —CH₃ piperonyl a mixture of the rotational isomers (DMSO-d₆) 2.07-2.43 (7H, m), 3.24- 3.57(11H, m), 5.17(2H, brs), 5.95- 5.99(2H, m), 6.66-6.89(3H, m), 7.07- 7.12(2H, m), 7.16-7.37(4H, m), 7.66(2H, d, J = 8.4 Hz), 7.85- 8.00(1H, m), 8.22(1H, d, J = 2.0 Hz). 810 4-CF₃PhOCH₂— —CH₃ —CH₃ 3,4-(CH₃O)₂PhCH₂— a mixture of the rotational isomers (DMSO-d₆) 2.07-2.43(7H, m), 3.26- 3.75(15H, m), 5.17(2H, brs), 6.70- 6.91(3H, m), 7.07-7.12(2H, m), 7.16- 7.37(4H, m), 7.66(2H, d, J = 8.9 Hz), 7.95-8.00(1H, m), 8.22(1H, d, J = 2.0 Hz).

TABLE 212

Example No. R₆₉₄ ¹H NMR (CDCl₃) δppm 811 piperonyl 2.18(3H, s), 2.49-2.54(4H, m), 3.45(2H, s), 3.70-3.74(2H, m), 4.23-4.27(2H, m), 5.03(2H, s), 5.95(2H, s), 6.71- 6.78(2H, m), 6.86(1H, brs), 6.92(1H, d, J = 8.6 Hz), 7.00- 7.06(3H, m), 7.44(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.54- 7.58(3H, m), 7.77(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.20(1H, d, J = 2.3 Hz), 9.20(1H, brs). 812 3,4-(CH3O)₂PhCH₂— 2.18(3H, s), 2.50-2.55(4H, m), 3.48(2H, s), 3.71-3.75(2H, m), 3.88(3H, s), 3.90(3H, s), 4.24-4.28(2H, m), 5.03(2H, s), 6.79-6.86(2H, m), 6.88(1H, brs), 6.93(1H, d, J = 8.4 Hz), 7.00-7.06(3H, m), 7.44(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.54- 7.58(3H, m), 7.77(1H, dd, J = 8.4 Hz, 2.5 Hz), 8.20(1H, d, J = 2.5 Hz), 9.19(1H, brs). 813 4-pyridylmethyl 2.18(3H, s), 2.52-2.58(4H, m), 3.55(2H, s), 3.73-3.77(2H, m), 4.27-4.31(2H, m), 5.03(2H, s), 6.93(1H, d, J = 8.4 Hz), 7.00-7.06(3H, m), 7.28(2H, d, J = 5.9 Hz), 7.44(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.54-7.57(3H, m), 7.77(1H, dd, J = 8.4 Hz, 2.3 Hz), 8.19(1H, d, J = 2.1 Hz), 8.56(2H, d, J = 5.9 Hz), 9.23(1H, brs).

TABLE 213

Example No. R₆₉₅ R₆₉₆ ¹H NMR (CDCl₃) δppm 814 —H piperonyl 2.42(4H, brs), 3.21(3H, s), 3.37(2H, brs), 3.42(2H, s), 3.62(2H, brs), 4.54(2H, s), 5.06(2H, s), 5.94(2H, s), 6.70-6.77(2H, m), 6.83(1H, brs), 6.98-7.04(3H, m), 7.14(2H, d, J = 8.7 Hz), 7.56(2H, d, J = 8.7 Hz), 7.62(2H, d, J = 8.9 Hz), 7.81(1H, dd, J = 8.4 Hz, 2.3 Hz), 8.23(1H, d, J = 2.1 Hz). 815 —H 4-pyridylmethyl 2.48(4H, brs), 3.21(3H, s), 3.41(2H, brs), 3.53(2H, s), 3.65(2H, brs), 4.55(2H, s), 5.06(2H, s), 7.01(1H, d, J = 8.2 Hz), 7.03(2H, d, J = 8.4 Hz), 7.14(2H, d, J = 8.9 Hz), 7.26-7.28(2H, m), 7.57(2H, d, J = 8.7 Hz), 7.62(2H, d, J = 8.7 Hz), 7.81(1H, dd, J = 8.4 Hz, 2.3 Hz), 8.23(1H, d, J = 2.1 Hz), 8.56(2H, d, J = 5.6 Hz). 816 —CH₃ piperonyl 2.18(3H, s), 2.41-2.44(4H, m), 3.22(3H, s), 3.36- 3.39(2H, m), 3.43(2H, s), 3.60-3.64(2H, m), 4.54(2H, s), 5.05(2H, s), 5.94(2H, s), 6.73-6.74(2H, m), 6.84(1H, brs), 6.97(1H, d, J = 8.4 Hz), 7.02(1H, d, J = 8.6 Hz), 7.04(2H, d, J = 8.6 Hz), 7.45(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.49(1H, d, J = 2.5 Hz), 7.56(2H, d, J = 8.4 Hz), 7.80(1H, dd, J = 8.6 Hz, 2.5 Hz). 8.20(1H, d, J = 2.0 Hz). 817 —CH₃ 3,4-(CH₃O)₂PhCH₂— 2.18(3H, s), 2.44(4H, brs), 3.22(3H, s), 3.38- 3.40(2H, m), 3.46(2H, s), 3.63-3.65(2H, m), 3.87(3H, s), 3.89(3H, s), 4.55(2H, s), 5.04(2H, s), 6.81(2H, brs), 6.87(1H, brs), 6.98(1H, d, J = 8.6 Hz), 7.02(1H, d, J = 8.4 Hz), 7.04(2H, d, J = 8.4 Hz), 7.45(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.49(1H, d, J = 2.6 Hz), 7.56(2H, d, J = 8.4 Hz), 7.80(1H, dd, J = 8.4 Hz, 2.5 Hz), 8.20(1H, d, J = 2.3 Hz).

TABLE 214

Example No. R₆₉₇ R₆₉₈ mp (° C.) 818 4-CF₃PhCO—

207.0-209.0 819 4-CF₃PhCO—

237.0-238.0 820 3,4-Cl₂PhSO₂—

115.0-116.0 821 3,4-Cl₂PhNHCO— —CH₂CONHPh 147.0-148.0 822 3,4-Cl₂PhNHCO—

207.0-208.0

TABLE 215

Example No. R₆₉₉ ¹H NMR or MS 823

¹H NMR (DMSO-d₆) δ 1.40-1.80(2H, m), 1.80-2.10 (2H, m), 2.93(3H, s), 3.15-3.50(2H, m), 3.60-3.90(2H, m), 4.31(2H, s), 4.60-4.70(1H, m), 6.35-6.45(1H, m), 6.54 (1H, dd, J = 14.4 Hz, 2.6 Hz), 6.96-7.11(4H, m), 7.27-7.31(2H, m), 7.52(1H, dd, J = 8.7 Hz, 2.7 Hz), 7.63 (1H, dd, J = 8.5 Hz, 2.1 Hz), 7.76(1H, d, J = 2.7 Hz), 7.84-7.88(2H, m), 10.39(1H, brs). 824

MS 682(M⁺ + H) 825

MS 618(M⁺ + H) 826 —N[CH₂CH(CH₃)₂]₂ MS 611(M⁺ + H) 827

MS 571(M⁺ + H) 828

MS 635(M⁺ + H) 829 —N[(CH₂)₃N(CH₃)₂]₂ MS 669(M⁺ + H) 830

MS 645(M⁺ + H) 831

MS 712(M⁺ + H) 832

MS 665(M⁺ + H) 833

MS 595(M⁺ + H) 834

MS 764(M⁺ + H)

TABLE 216

Example No. R₇₀₀ MS (M⁺ + H) 835

635 836

714 837

581 838 4-CF₃OPhCH₂NH— 673 839

553 840 —NH(CH₂)₅OH 585 841 —NHCH(CH₃)COOCH₃ 585 842 3,5-F₂PhCH₂N(C₂H₅)— 653 843 4-CH₃PhNHCOCH₂N(CH₃)— 660 844 3,4-(CH₃O)₂PhCH₂N(C₂H₅)— 677 845 4-CH₃PhCH₂N(C₂H₅)— 631 846

614 847

686 848 3,4-Cl₂Ph— 714 849

695 850

734 851 —N(CH₂Ph)CH₂CH₂CN 642 852 —N(C₂H₅)CH(CH₃)₂ 569 853 —NHC(CH₃)₂CH₂Ph 631 854 3-CNPhNH— 600 855 3,5-F₂PhNH— 611

TABLE 217

Example No. R₇₀₁ MS (M⁺ + H) 856

700 857

652 858

583 859

662 860

665 861

659 862

673 863

702 864

674 865

674 866

666

TABLE 218

Example No. R₇₀₂ MS (M⁺ + H) 867

698 868

639 869

639 870

673 871

610 872

596 873

555 874

569 875

663 876

692

TABLE 219

Example MS No. R₇₀₃ R₇₀₄ R₇₀₅ R₇₀₆ (M⁺ + H) 877 —H —H —OCF₃ —H 659 878 —H —H —CH₃ —H 589 879 —OCH₃ —OCH₃ —H —H 635 880 —H —H —SCH₃ —H 621 881 —CH(CH₃)₂ —H —H —H 617 882 —H —H cyclohexyl —H 657 883 —NHPh —H —Cl —H 702 884 4-ClPhNH— —H —H —COOC₂H₅ 774 885 —H —H —O(CH₂)₂N(C₂H₅)₂ —H 690 886 —H —H

—H 673 887 —H —H

—H 658 888 —H —H —NHSO₂CH₃ —H 668 889 —H —H —(CH₂)₂OH —H 619 890 —H —H —(CH₂)₄CH₃ —H 645 891 —H —H benzyl —H 665 892 —H —H —SPh —H 683 893 —H —H

—H 709

TABLE 220

Example No. R₇₀₇ R₇₀₈ R₇₀₉ ¹H NMR (CDCl₃) δppm 894 4-CF₃Ph— —CH₃ piperonyl 1.34-1.42(2H, m), 1.80-1.98(3H, m), 2.03(3H, s), 2.29(2H, d, J = 6.6 Hz), 2.41(4H, brs), 2.65(2H, t, J = 12.0 Hz), 3.43(2H, s), 3.49- 3.65(6H, m), 5.94(2H, s), 6.69-6.87(8H, m), 7.56(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.68(2H, d, J = 8.6 Hz), 7.76-7.85(3H, m). 895 3,4-Cl₂Ph— —CH₃ piperonyl 1.34-1.39(2H, m), 1.79-1.98(3H, m), 2.04(3H, s), 2.29(2H, d, J = 6.6 Hz), 2.41(4H, brs), 2.64(2H, t, J = 11.9 Hz), 3.43(2H, s), 3.49- 3.65(6H, m), 5.94(2H, s), 6.70-6.88(7H, m), 7.45-7.50(3H, m), 7.55(1H, dd, J = 8.9 Hz. 2.8 Hz), 7.78-7.82(2H, m). 896 4-CF₃Ph— —CH₃ benzyl 1.34-1.43(2H, m), 1.80-2.01(3H, m), 2.03(3H, s), 2.29(2H, d, J = 6.6 Hz), 2.43(4H, brs), 2.65(2H, t, J = 12.0 Hz), 3.49-3.65(8H, m), 6.70-6.76(3H, m), 6.86(1H, d, J = 8.7 Hz), 7.26-7.32 (6H, m), 7.55(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.68(2H, d, J = 8.6 Hz), 7.76(1H, d, J = 2.8 Hz), 7.84(2H, d, J = 8.4 Hz). 897 3,4-Cl₂Ph— —CH₃ benzyl 1.27-1.39(2H, m), 1.79-2.01(3H, m), 2.04(3H, s), 2.29(2H, d, J = 6.8 Hz), 2.43(4H, brs), 2.64(2H, t, J = 11.9 Hz), 3.53-3.66(8H, m), 6.69-6.76(3H, m), 6.86(1H, d, J = 8.7 Hz), 7.29-7.32 (6H, m), 7.44-7.50(2H, m), 7.55(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.79-7.82(2H, m). 898 4-CF₃Ph— —H 3,4-Cl₂Ph— 1.34-1.46(2H, m), 1.83-2.02(3H, m), 2.34(2H, d, J = 6.8 Hz), 2.67(2H, t, J = 12.0 Hz), 3.15- 3.17(4H, m), 3.55-3.65(4H, m), 3.78-3.80(2H, m), 6.72-6.97(7H, m), 7.26-7.31(2H, m), 7.56 (1H, dd, J = 8.9 Hz, 2.8 Hz), 7.70(2H, d, J = 8.24 Hz), 7.78-7.86(3H, m). 899 4-CF₃Ph— —H 4-CF₃Ph— 1.35-1.47(2H, m), 1.83-2.02(3H, m), 2.36(2H, d, J = 6.8 Hz), 2.67(2H, t, J = 12.0 Hz), 3.28- 3.30(4H, m), 3.57(2H, d, J = 12.2 Hz), 3.68(2H, brs), 3.82(2H, brs), 6.76(1H, d, J = 8.7 Hz), 6.87-6.96(7H, m), 7.50(2H, d, J = 8.6 Hz), 7.56(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.69(2H, d, J = 8.4 Hz), 7.80-7.86(3H, m). 900 3,4-Cl₂Ph— —H 4-CF₃Ph— 1.34-1.47(2H, m), 1.83-2.02(3H, m), 2.35(2H, d, J = 6.8 Hz), 2.68(2H, t, J = 12.0 Hz), 3.29- 3.31(4H, m), 3.58(2H, d, J = 12.2 Hz), 3.68(2H, brs), 3.83(2H, brs), 6.79(1H, d, J = 8.7 Hz), 6.88-6.98(7H, m), 7.50-7.59(5H, m), 7.79(1H, d, J = 2.8 Hz), 7.83-7.84(1H, m).

TABLE 221

Example No. R₇₁₀ R₇₁₁ R₇₁₂ ¹H NMR (CDCl₃) δppm 901 3,4-Cl₂Ph— —H 3,4-Cl₂Ph— 1.34-1.46(2H, m), 1.82-2.02(3H, m), 2.35(2H, d, J = 6.6 Hz), 2.66(2H, t, J = 12.0 Hz), 3.16- 3.17(4H, m), 3.57(2H, d, J = 12.2 Hz), 3.65(2H, brs), 3.80(2H, brs), 6.72-6.78(2H, m), 6.87- 6.97(6H, m), 7.29(1H, d, J = 8.9 Hz), 7.49(2H, s), 7.57(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.81- 7.84(2H, m). 902 4-CF₃Ph— —CH₃ 3,4-Cl₂Ph— 1.34-1.46(2H, m), 1.82-2.01(3H, m), 2.03(3H, s), 2.35(2H, d, J = 6.8 Hz), 2.67(2H, t, J = 12.0 Hz), 3.15-3.17(4H, m), 3.58(2H, d, J = 12.2 Hz), 3.65(2H, brs), 3.79(2H, brs), 6.70-6.76 (4H, m), 6.86(1H, d, J = 8.6 Hz), 6.96(1H, d, J = 2.8 Hz), 7.29(1H, d, J = 8.7 Hz), 7.53-7.57(1H, m), 7.68(2H, d, J = 8.2 Hz), 7.77(1H, d, J = 2.5 Hz), 7.84(2H, d, J = 8.2 Hz), 8.05(1H, s). 903 4-CF₃Ph— —H piperonyl 1.27-1.41(2H, m), 1.83-2.05(3H, m), 2.29(2H, d, J = 6.8 Hz), 2.40-2.44(4H, m), 2.66-2.75(2H, m), 3.44-3.56(4H, m), 3.65-3.74(4H, m), 5.95(2H, s), 6.75-6.99(8H, m), 7.57(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.71-7.74(4H, m), 7.85(2H, d, J = 8.2 Hz). 904 3,4-Cl₂Ph— —H benzyl 1.31-1.40(2H, m), 1.80-2.05(3H, m), 2.29(2H, d, J = 6.8 Hz), 2.62-2.71(2H, m), 3.53-3.58(6H, m), 3.66(2H, brs), 6.79(1H, d, J = 8.7 Hz), 6.88- 6.98(4H, m), 7.31(5H, brs), 7.50(2H, s), 7.56 (1H, dd, J = 8.9 Hz, 2.8 Hz), 7.77-7.84(3H, m). 905 4-CF₃Ph— —H benzyl 1.30-1.43(2H, m), 1.80-2.04(3H, m), 2.28(2H, d, J = 6.8 Hz), 2.42-2.46(4H, m), 2.62-2.70(2H, m), 3.47-3.58(6H, m), 3.66(2H, brs), 6.78(1H, d, J =8.7 Hz), 6.87-6.97(4H, m), 7.26-7.32 (6H, m), 7.56(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.68- 7.77(3H, m), 7.83-7.86(2H, m). 906 3,4-Cl₂Ph— —H piperonyl 1.33-1.39(2H, m), 1.79-2.00(3H, m), 2.30(2H, d, J = 6.8 Hz), 2.42-2.44(4H, m), 2.65(2H, t, J = 10.4 Hz), 3.43(2H, s), 3.49-3.57(4H, m), 3.65(2H, brs), 5.94(2H, s), 6.74-6.77(3H, m), 6.84-6.97(5H, m), 7.49-7.59(3H, m), 7.81- 7.85(3H, m). 907 4-CF₃Ph— —OCH₃ piperonyl 1.33-1.44(2H, m), 1.82-1.95(3H, m), 2.29(2H, d, J = 6.8 Hz), 2.41(4H, brs), 2.70(2H, t, J = 12.2 Hz), 3.43-3.64(8H, m), 3.67(3H, s), 5.94(2H, s), 6.46(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.54(1H, d, J = 2.5 Hz), 6.70-6.78(4H, m), 6.85(1H, s), 6.92(1H, d, J = 8.6 Hz), 7.55(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.67(2H, d, J = 8.4 Hz), 7.74(1H, d, J = 2.6 Hz), 7.84(2H, d, J = 8.2 Hz).

TABLE 222

Example No. R₇₁₃ R₇₁₄ R₇₁₅ ¹H NMR (CDCl₃) δppm 908 3,4-Cl₂Ph— —H benzyl 1.76-1.99(4H, m), 2.45-2.73(7H, m), 3.53(4H, brs), 3.66(4H, brs), 6.75(1H, d, J = 8.7 Hz), 6.87-6.97(4H, m), 7.29-7.59(9H, m), 7.83(2H, d, J = 2.0 Hz). 909 4-CF₃Ph— —H benzyl 1.77-1.99(4H, m), 2.45(4H, brs), 2.53-2.76(3H, m), 3.54(4H, brs), 3.65-3.69(4H, m), 6.81(1H, d, J = 8.7 Hz), 6.90-6.99(4H, m), 7.28-7.34(6H, m), 7.57(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.71- 7.75(3H, m), 7.85(2H, d, J = 8.2 Hz). 910 4-CF₃Ph— —CH₃ piperonyl 1.75-1.96(4H, m), 2.04(3H, s), 2.44(4H, brs), 2.53-2.73(3H, m), 3.43(2H, s), 3.53(2H, brs), 3.63(4H, brs), 5.94(2H, s), 6.70-6.89(8H, m), 7.56(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.67(2H, d, J = 8.6 Hz), 7.78(1H, d, J = 2.6 Hz), 7.84(2H, d, J = 8.2 Hz). 911 4-CF₃Ph— —CH₃ benzyl 1.75-2.02(4H, m), 2.03(3H, s), 2.45(4H, brs), 2.55-2.72(3H, m), 3.53(4H, brs), 3.66(4H, brs), 6.72-6.77(3H, m), 6.87(1H, d, J = 8.6 Hz), 7.25-7.31(6H, m), 7.56(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.66(2H, d, J = 8.2 Hz), 7.78-7.86(3H, m). 912 3,4-Cl₂Ph— —CH₃ piperonyl 1.76-1.98(4H, m), 2.04(3H, s), 2.44(4H, brs), 2.54-2.72(3H, m), 3.43(2H, s), 3.54(2H, brs), 3.63-3.67(4H, m), 5.94(2H, s), 6.70-6.89(8H, m), 7.44-7.59(3H, m), 7.80(2H, d, J = 2.0 Hz). 913 3,4-Cl₂Ph— —CH₃ benzyl 1.77-1.97(4H, m), 2.07(3H, s), 2.45(4H, brs), 2.53-2.75(3H, m), 3.54(4H, brs), 3.66(4H, brs), 6.75-6.81(3H, m), 6.90(1H, d, J = 8.6 Hz), 7.26-7.33(6H, m), 7.51-7.58(3H, m), 7.72(1H, d, J = 2.6 Hz), 7.79(1H, s). 914 3,4-Cl₂Ph— —H piperonyl 1.76-1.99(4H, m), 2.44(4H, brs), 2.54-2.74(3H, m), 3.43(2H, s), 3.54(2H, brs), 3.63-3.67(4H, m), 5.94(2H, s), 6.74-6.98(8H, m), 7.45- 7.59(3H, m) 7.81-7.84(3H, m). 915 4-CF₃Ph— —H piperonyl 1.76-1.80(2H, m), 1.91-1.95(2H, m), 2.43(4H, brs), 2.59-2.73(3H, m), 3.43(2H, s), 3.54(2H, brs), 3.62(4H, brs), 5.94(2H, s), 6.72-6.75(3H, m), 6.84-6.96(5H, m), 7.57(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.66(2H, d, J = 8.4 Hz), 7.82-7.87(4H, m).

TABLE 223

Example No. R₇₁₆ R₇₁₇ M ¹H NMR (CDCl₃) δppm 916 —H piperonyl 1 1.31-1.45(2H, m), 1.82-2.02(3H, m), 2.33(2H, d, J = 6.8 Hz), 2.43(4H, brs), 2.69(2H, t, J = 12.0 Hz), 3.43(2H, s), 3.51-3.67(6H, m), 5,93(2H, s), 6.73- 6.99(8H, m), 7.28(2H, d, J = 8.6 Hz), 7.50(2H, d, J = 8.6 Hz), 8.28(1H, d, J = 2.1 Hz), 8.43(1H, d, J = 2.1 Hz). 917 —H benzyl 1 1.34-1.44(2H, m), 1.82-2.00(3H, m), 2.32(2H, d, J = 6.8 Hz), 2.43-2.47(4H, m), 2.69(2H, t, J = 12.0 Hz), 3.51-3.67(8H, m), 6.88(2H, d, J = 9.2 Hz), 6.98(2H, d, J = 9.2 Hz), 7.25-7.32(8H, m), 7.50(2H, d, J = 8.6 Hz), 8.28(1H, d, J = 2.3 Hz), 8.43(1H, d, J = 2.1 Hz). 918 —CH₃ piperonyl 1 1.31-1.45(2H, m), 1.82-2.00(3H, m), 2.02(3H, s), 2.33(2H, d, J = 6.8 Hz), 2.43(4H, brs), 2.68(2H, t, J = 11.9 Hz), 3.41-3.67(8H, m), 5.92(2H, s), 6.73- 6.92(7H, m), 7.25-7.30(2H, m), 7.50(2H, d, J = 8.6 Hz), 8.30(1H, d, J = 2.3 Hz), 8.41(1H, d, J = 2.3 Hz). 919 —CH₃ benzyl 1 1.37-1.40(2H, m), 1.83-2.01(3H, m), 2.03(3H, s), 2.31(2H, d, J = 6.9 Hz), 2.43-2.47(4H, m), 2.70(2H, t, J = 12.0 Hz), 3.51-3.67(8H, m), 6.74-6.80(2H, m), 6.91(1H, d, J = 8.6 Hz), 7.24-7.33(8H, m), 7.52(2H, d, J = 8.4 Hz), 8.29(1H, d, J = 2.1 Hz), 8.42(1H, d, J = 2.3 Hz). 920 —H piperonyl 0 1.79-2.03(4H, m), 2.45(4H, brs), 2.57-2.76(3H, m), 3.44(2H, s), 3.55(2H, brs), 3.66(4H, brs), 5.94(2H, s), 6.72-6.78(2H, m), 6.85-7.00(6H, m), 7.28(2H, d, J = 8.6 Hz), 7.50(2H, d, J = 8.6 Hz), 8.28(1H, d, J = 2.1 Hz), 8.42(1H, d, J = 2.1 Hz).

TABLE 224

Example No. R₇₁₈ R₇₁₉ ¹H NMR (CDCl₃) δppm 921 3,4-Cl₂Ph— piperonyl 1.37-1.44(2H, m), 1.81-2.02(3H, m), 2.30(2H, d, J = 6.8 Hz), 2.42(4H, brs), 2.69(2H, t, J = 11.9 Hz), 3.43(2H, s), 3.43-3.65(6H, m), 3.68(3H, s), 5.94(2H, s), 6.46(1H, dd, J = 8.7 Hz, 2.5 Hz), 6.54(1H, d, J = 2.3 Hz), 6.73- 6.76(3H, m), 6.85(1H, s), 6.93(1H, d, J = 8.6 Hz), 7.44- 7.57(3H, m), 7.79-7.83(3H, m). 922 4-CF₃Ph— benzyl 1.37-1.44(2H, m), 1.81-2.02(3H, m), 2.29(2H, d, J = 6.8 Hz), 2.42-2.46(4H, m), 2.69(2H, t, J = 12.0 Hz), 3.48- 3.63(8H, m), 3.67(3H, s), 6.46(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.54(1H, d, J = 2.6 Hz), 6.75(1H, d, J = 8.9 Hz), 6.92(1H, d, J = 8.7 Hz), 7.26-7.36(6H, m), 7.54(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.67(2H, d, J = 8.6 Hz), 7.75(1H, d, J = 2.8 Hz), 7.83(2H, d, J = 8.1 Hz). 923 3,4-Cl₂Ph— benzyl 1.37-1.44(2H, m), 1.81-2.02(3H, m), 2.30(2H, d, J = 6.8 Hz), 2.42-2.46(4H, m), 2.69(2H, t, J = 11.9 Hz), 3.50- 3.66(8H, m), 3.67(3H, s), 6.45(1H, dd, J = 8.7 Hz, 2.5 Hz), 6.54(1H, d, J = 2.5 Hz), 6.74(1H, d, J = 8.7 Hz), 6.93(1H, d, J = 8.6 Hz), 7.26-7.32(5H, m), 7.43-7.56(3H, m), 7.79-7.83(3H, m).

TABLE 225

Example No. R₇₂₀ ¹H NMR (CDCl₃) δppm 924 benzyl 1.63-1.77(2H, m), 1.81-1.98(2H, m), 2.44(4H, brs), 2.53-2.72 (3H, m), 3.53(4H, brs), 3.65-3.69(4H, m), 6.90-7.04(5H, m), 7.26-7.33(5H, m), 7.74(2H, d, J = 8.2 Hz), 7.99(2H, d, J = 8.2 Hz), 8.14-8.19(2H, m), 8.27(1H, d, J = 2.6 Hz). 925 piperonyl 1.64-1.77(2H, m), 1.89-1.97(2H, m), 2.39-2.41 (4H, m), 2.56-2.75(3H, m), 3.43(2H, s), 3.52-3.69(6H, m), 5.94(2H, s), 6.70-6.77(2H, m), 6.85- 7.04(6H, m), 7.74(2H, d, J = 8.2 Hz), 7.99(2H, d, J = 8.2 Hz), 8.14- 8.18(2H, m), 8.27(1H, d, J = 2.5 Hz).

The following compounds were made in the same manner as in Reference Example 918.

TABLE 226

Example No. R₇₂₁ Xb₉ R₇₂₂ M ¹H NMR (CDCl₃) δppm 926 4-CF₃Ph— —CH₂— benzyl 1 2.38-2.44(4H, m), 2.63-2.68(2H, m), 2.89- 2.95(2H, m), 3.45-3.49(2H, m), 3.52(2H, s), 3.64-3.68(2H, m), 6.85(1H, d, J = 8.9 Hz), 6.93-6.98(2H, m), 7.08-7.13 (2H, m), 7.28-7.36(5H, m), 7.44-7.51(4H, m), 7.96 (1H, d, J = 2.5 Hz), 8.00-8.04(1H, m), 8.14(1H, s), 8.18(1H, s). 927 3,4-Cl₂Ph— —CH(CH₃)— piperonyl 0 1.47(3H, d, J = 6.8 Hz), 2.00-2.15(1H, m), 2.25-2.50 (3H, m), 3.36(2H, s), 3.36- 3.80(4H, m), 3.98(1H, q, J = 6.8 Hz), 5.93(2H, s), 6.65-6.75(2H, m), 6.79(1H, d, J = 1.2Hz), 6.89(1H, d, J = 8.8 Hz), 7.02- 7.06(2H, m), 7.16-7.33(4H, m), 7.57(1H, d, J = 2.4 Hz), 7.91 (1H, d, J = 2.7 Hz), 8.00(1H, brs), 8.05-8.10(2H, m). 928 3,4-Cl₂Ph— —C(CH₃)₂— piperonyl 0 1.55(6H, s), 1.80-2.15(2H, m), 2.20- 2.55(2H, m), 2.95-3.20(2H, m), 3.31(2H, s), 3.50-3.90(2H, m), 5.91(2H, s), 6.60-6.72 (2H, m), 6.76(1H, d, J = 1.3 Hz), 6.90(1H, d, J = 8.9 Hz), 7.07-7.33(6H, m), 7.58 (1H, d, J = 2.4 Hz), 7.88(1H, d, J = 2.7 Hz), 8.09- 8.11(2H, m), 8.17(1H, dd, J = 8.9 Hz, 2.8 Hz).

TABLE 227

Example No. R₇₂₃ ¹H NMR (CDCl₃) δppm 929 benzyl 2.33-2.55 (4H, m), 3.36-3.79(6H, m), 6.89(1H, d, J = 8.7 Hz), 7.07- 7.15(3H, m), 7.24-7.38(6H, m), 7.67-7.70(2H, m), 8.00(2H, d, J = 7.9 Hz), 8.09-8.13(1H, m), 8.32(1H, d, J = 2.3 Hz), 9.05(1H, brs). 930 piperonyl 2.36-2.44(4H, m), 3.37-3.76(6H, m), 5.93(2H, s), 6.69-6.75(2H, m), 6.83(1H, brs), 6.86(1H, d, J = 8.7 Hz), 7.04-7.06(2H, m), 7.10- 7.14(1H, m), 7.27-7.36(1H, m), 7.65(2H, d, J = 8.4 Hz), 7.99(2H, d, J = 8.1 Hz), 8.07-8.12(1H, m), 8.34(1H, d, J = 2.6 Hz), 9.41(1H, s).

TABLE 228

Example No. R₇₂₄ ¹H NMR (CDCl₃) δppm 931 4-CF₃PhCH₂N(SO₂CH₃)— 2.31-2.41(4H, m), 2.58-2.64(2H, m), 2.94-2.97 (2H, m), 2.99(3H, s), 3.38-3.41(4H, m), 3.60-3.65(2H, m), 4.85(2H, s), 5.94(2H, s), 6.65-6.75(2H, m), 6.83- 6.87(2H, m), 6.95-7.05(2H, m), 7.20-7.30(2H, m), 7.38- 7.41(2H, m), 7.52(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.54- 7.57(2H, m), 8.04(1H, d, J = 2.3 Hz). 2.25-2.45(4H, m), 2.59-2.65(2H, m), 2.94-3.05 (5H, m), 932 3,4-Cl₂PhCH₂N(SO₂CH₃)— 3.30-3.45(4H, m), 3.55-3.70(2H, m), 4.74(2H, s), 5.95(2H, s), 6.65-6.80(2H, m), 6.84-6.89(2H, m), 7.02- 7.15(3H, m), 7.23-7.30(3H, m), 7.30-7.40(2H, m), 8.03(1H, d, J = 2.7 Hz). 933 3,4-Cl₂PhCH₂NHCO— 2.25-2.45(4H, m), 2.59-2.65(2H, m), 2.94-3.00(2H, m), 3.37-3.41(4H, m), 3.59-3.65(2H, m), 4.58(2H, d, J = 5.9 Hz), 5.94(2H, s), 6.50-6.65(1H, m), 6.65-6.80(2H, m), 6.84(1H, s), 6.94 (1H, d, J = 8.6 Hz), 7.03-7.06(2H, m), 7.17(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.22-7.26(2H, m), 7.38-7.42(2H, m), 8.14(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.57(1H, d, J = 2.3 Hz). 934 3,4-Cl₂PhNHCON(C₂H₅)— 1.17(3H, t, J = 7.1 Hz , 2.32-2.42 (4H, m), 2.61- 2.67(2H, m), 2.97-3.03(2H, m), 3.39-3.43(4H, m), 3.61- 3.65(2H, m), 3.74(2H, q, J = 7.1 Hz), 5.94(2H, s), 6.00(1H, brs), 6.70-6.85(3H, m), 7.05(1H, d, J = 8.7 Hz), 7.09-7.13(3H, m), 7.26-7.31(3H, m), 7.52(1H, d, J = 2.5 Hz), 7.61(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.12(1H, d, J = 2.4 Hz). 935 3,4-Cl₂PhN(CH₃)— 2.25-2.45(4H, m), 2.59-2.65(2H, m), 2.95-3.00(2H, m), 3.25(3H, s), 3.38-3.42(4H, m), 3.61-3.65(2H, m), 5.94(2H, s), 6.55-6.65(1H, m), 6.65-6.80(2H, m), 6.80- 6.85(2H, m), 6.89-6.93(1H, m), 7.06-7.10(2H, m), 7.20- 7.27(3H, m), 7.45-7.50(1H, m), 8.01(1H, d, J = 2.4 Hz). 936 3,4-Cl₂PhNH— 2.31-2.41(4H, m), 2.59-2.65(2H, m), 2.94-3.00(2H, m), 3.37-3.41(4H, m), 3.61-3.65(2H, m), 5.61(1H, brs), 5.94(2H, s), 6.69-6.80(3H, m), 6.84(1H, s), 6.90(1H, d , J = 8.7 Hz), 6.96(1H, d, J = 2.7 Hz), 7.04-7.07(2H, m), 7.21-7.25(3H, m), 7.49(1H, dd, J = 8.7 Hz, 2.9 Hz), 8.00(1H, d, J = 2.8 Hz). 937 4-CF₃PhCH₂NHCO— 2.31-2.40(4H, m), 2.59-2.65(2H, m), 2.95-3.01(2H, m), 3.38-3.41(4H, m), 3.60-3.64(2H,m), 4.70(2H, d, J = 5.8 Hz), 5.94(2H, s), 6.35-6.50(1H, m), 6.70-6.77(2H, m), 6.84(1H, s), 6.95 (1H, d, J = 8.6 Hz), 7.03-7.07(2H, m), 7.23-7.26(2H, m), 7.44-7.47(2H, m), 7.59-7.62(2H, m), 8.14(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.57(1H, d, J = 2.4 Hz). 938 3,4-Cl₂PhN(C₂H₅)CONH— 1.17 (3H, t, J = 7.1 Hz), 2.30-2.40(4H, m), 2.57- 2.63(2H, m), 2.92-2.98(2H, m), 3.37-3.40(4H, m), 3.60- 3.64(2H, m), 3.77(2H, q, J = 7.1 Hz), 5.94(2H, s), 6.65- 6.80(2H, m), 6.81-6.85(2H, m), 6.98-7.00(2H, m), 7.17- 7.21(3H, m), 7.45(1H, d, J = 2.4 Hz), 7.57(1H, d, J = 8.5 Hz), 7.85-7.91(2H, m).

TABLE 229

Example No. R₇₂₅ R₇₂₆ ¹H NMR (CDCl₃) δppm 939 3,4-Cl₂PhNHCO— —CH₃ 2.30-2.50(4H, m), 2.78(3H, s), 3.42(2H, s), 3.50- 3.65(4H, m), 3.82(2H, s), 5.95(2H, s), 6.65- 6.75(2H, m), 6.85(1H, s), 7.05(1H, d, J = 8.6 Hz), 7.26-7.30(1H, m), 7.39-7.43(2H, m), 7.49- 7.53(2H, m), 7.88(1H, d, J = 2.4 Hz), 8.24(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.31(1H, brs), 8.66(1H, d, J = 2.4 Hz). 940 4-CF₃PhNHCO— —CH₃ 2.30-2.45(4H, m), 2.78(3H, s), 3.41(2H, s), 3.55- 3.59(4H, m), 3.82(2H, s), 5.94(2H, s), 6.65- 6.80(2H, m), 6.85(1H, s), 7.05(1H, d, J = 8.6 Hz), 7.26-7.30(1H, m), 7.41(1H, d, J = 2.8 Hz), 7.51(1H, d, J = 8.8 Hz), 7.59-7.63(2H, m), 7.77- 7.80(2H, m), 8.26(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.54(1H, brs), 8.66(1 H, d, J = 2.2 Hz). 941 3,4-Cl₂PhCH₂NHCO— —CH₃ 2.30-2.45(4H, m), 2.80(3H, s), 3.42(2H, s), 3.50- 3.65(4H, m), 3.81(2H, s), 4.59(2H, d, J = 5.9 Hz), 5.95(2H, s), 6.50-6.60(1H, m), 6.65- 6.80(2H, m), 6.85(1H, s), 7.01(1H, d, J = 8.6 Hz), 7.18(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.30(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.39-7.43(3H, m), 7.54(1H, d, J = 8.8 Hz), 8.18(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.56(1H, d, J = 2.4 Hz). 942 4-CF₃PhCH₂NHCO— —CH₃ 2.30-2.45(4H, m), 2.80(3H, s), 3.42(2H, s), 3.50- 3.65(4H, m), 3.81(2H, s), 4.70(2H, d, J = 5.9 Hz), 5.94(2H, s), 6.50-6.65(1H, m), 6.70- 6.80(2H, m), 6.85(1H, s), 7.00(1H, d, J =8.6 Hz), 7.29(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.39- 7.62(6H, m), 8.18(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.57(1H, d, J = 2.4 Hz). 943 3,4-Cl₂PhN(CH₃)— —C₂H₅ 1.02(3H, t, J = 7.1 Hz), 2.35-2.40(4H, m), 3.22(2H, q, J = 7.1 Hz), 3.27(3H, s), 3.40(2H, s), 3.45-3.60(4H, m), 3.85(2H, s), 5.94(2H, s), 6.64(1H, dd, J = 8.9 Hz, 2.9 Hz), 6.65-6.75(2H, m), 6.84(1H, s), 6.90(1H, d, J = 2.8 Hz), 6.96(1H, d, J = 8.7 Hz), 7.22-7.26(1H, m), 7.26- 7.35(1H, m), 7.42(1H, d, J = 2.8 Hz), 7.50(1H, dd, J = 8.7 Hz, 2.9 Hz), 7.66(1H, d, J = 8.8 Hz), 8.00(1H, d, J = 2.6 Hz).

Example No. R₇₂₇ R₇₂₈ R₇₂₉ R₇₃₀ R₇₃₁ Xb₁₀ ¹H NMR (CDCl₃) δppm 944 —Cl —Cl —CH₃ —CH₃ —H —N(CH₃)— 2.30(6H, s), 2.32-2.45(4H, m), 2.83(3H, s), 3.30-3.45(4H, m), 3.55- 3.70(2H, m), 3.83(2H, s), 5.94(2H, s), 6.69-6.76(4H, m), 6.83(1H, s), 6.96(1H, d, J = 8.6 Hz), 7.40(1H, d, J = 8.7 Hz), 7.50(1H, dd, J = 8.8 Hz, 2.5 Hz), 7.87(1H, d, J = 2.4 Hz), 8.19(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.31(1H, brs), 8.68(1H, d, J = 2.2 Hz). 945 —CF₃ —H —CH₃ —CH₃ —H —N(CH₃)— 2.30-2.45(10H, m), 2.86(3H, s), 3.30- 3.45(4H, m), 3.55-3.70(2H, m), 3.84(2H, s), 5.94(2H, s), 6.65- 6.78(4H, m), 6.84(1H, s), 6.99(1H, d, J = 8.6 Hz), 7.60-7.65(2H, m), 7.70- 7.78(2H, m), 8.07(1H, brs), 8.21(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.70(1H, d, J = 2.5 Hz). 946 —CF₃ —H —H —H —H —CH(CH₃)— 1.30-1.36(3H, m), 2.10-2.40(4H, m), 2.47-2.67(2H, m), 3.25-3.45(5H, m), 3.50-3.65(2H, m), 5.93(2H, s), 6.65- 6.75(2H, m), 6.83(1H, d, J = 0.9 Hz), 7.01(1H, dd, J = 8.6 Hz, 0.6 Hz), 7.06-7.15(2H, m), 7.25-7.30 (2H, m), 7.60-7.64(2H, m), 7.74-7.78(2H, m), 8.14(1H, brs), 8.22(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.67-8.68(1H, m). 947 —CF₃ —H —H —H —CH₃ —CH₂— 1.14-1.17(3H, m), 1.95-2.10(1H, m), 2.15-2.45(3H, m), 2.55-2.70(1H, m), 2.85-3.05(2H, m), 3.15-3.45(4H, m), 3.45-3.70(2H, m), 5.92-5.94(2H, m), 6.65-6.85(3H, m), 6.95-7.06(3H, m), 7.10-7.30(2H, m), 7.59-7.63(2H, m), 7.75-7.79(2H, m), 8.24(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.40(1H, brs), 8.71(1H, d, J = 2.4 Hz).

TABLE 231

Example No. R₇₃₂ ¹H NMR (DMSO-d₆) δppm 948 —Br 2.20-2.35(4H, m), 2.59-2.65(2H, m), 2.79-2.85(2H, m), 3.20-3.60(6H, m), 5.99(2H, s), 6.73-6.77(1H, m), 6.83-6.86(2H, m), 7.07-7.10(2H, m), 7.27-7.34(4H, m), 7.62-7.65(2H, m), 8.44-8.48(2H, m), 10.90(1H, brs). 949 —H 2.20-2.35(4H, m), 2.59-2.65(2H, m), 2.78-2.84(2H, m), 3.38-3.44(6H, m), 5.98(2H, s), 6.72-6.76(1H, m), 6.82-6.86(2H, m), 7.04-7.08(2H, m), 7.17(1H, d, J = 8.8 Hz), 7.26-7.33(4H, m), 7.61-7.65(2H, m), 8.17(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.55(1H, d, J = 2.6 Hz), 10.98(1H, brs).

Example 950 Production of 3,4-dichloro-N-{6-[4-(4-phenethylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}benzamide

To a solution of ethyl 4-(5-aminopyridin-2-yloxy)benzoate (690 mg, 2.7 mmol) in THF (10 mL) were added triethylamine (0.73 mL, 5.3 mmol) and 3,4-dichlorobenzoyl chloride (570 mg, 2.7 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling. This reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The resulting solution was washed with water, 1 N hydrochloric acid and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was washed, when hot, with n-hexane:dichloromethane=1:2. The product was dissolved in THF (20 mL). To the residue was added 1 N aqueous sodium hydroxide (2.9 mL, 2.9 mmol), and this solution was stirred for 5 hours at 100° C. THF was evaporated, and the aqueous layer was made to have a pH of 3 with 1 N hydrochloric acid. Precipitated matter was collected by filtration, and dried. The resulting product was dissolved in DMF (10 mL), and 1-phenethylpiperazine (200 mg, 1.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.3 mmol) and 1-hydroxybenzotriazole monohydrate (170 mg, 1.3 mmol) were added to the solution. The resulting solution was stirred for 1 day at room temperature. This reaction solution was concentrated under reduced pressure, and to the residue was added chloroform. The resulting solution was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (methanol:chloroform=1:99), to thereby yield 310 mg of the title compound.

Appearance: White Powder

¹H NMR (CDCl₃) δ 2.54 (4H, brs), 2.62-2.68 (2H, m), 2.79-2.85 (2H, m), 3.60-3.73 (4H, m), 6.95 (1H, d, J=8.9 Hz), 7.09-7.23 (5H, m), 7.27-7.33 (2H, m), 7.37-7.41 (2H, m), 7.55 (1H, d, J=8.3 Hz), 7.74-7.78 (1H, m), 8.04 (1H, d, J=2.0 Hz), 8.11-8.15 (1H, m), 8.31 (1H, d, J=2.6 Hz), 8.57 (1H, brs).

The following compounds were produced in the same manner as in Example 950.

TABLE 232

Example No. R₇₃₃ R₇₃₄ R₇₃₅ R₇₃₆ R₇₃₇ MS (M⁺ + H) 951 —CH₃ —F —H —H 4-CNPhCH₂— 550 952 —H —F —F —H 4-CNPhCH₂— 554 953 —H —Cl —H —Cl 4-CNPhCH₂— 586 954 —H —OCF₃ —H —H 4-CNPhCH₂— 602 955 —CH₃ —F —H —H 2-pyridylmethyl 526 956 —H —CH₃ —CH₃ —H 2-pyridylmethyl 522 957 —H —F —F —H 2-pyridylmethyl 530 958 —H —Cl —H —Cl 2-pyridylmethyl 530 959 —H —CF₃ —H —H 2-pyridylmethyl 562 960 —H —H —Cl —H 2-pyridylmethyl 528 961 —H —CF₃ —H —F 2-pyridylmethyl 580 962 —H —OCF₃ —H —H 2-pyridylmethyl 578 963 —CH₃ —F —H —H 3-pyridylmethyl 526 964 —H —CH₃ —CH₃ —H 3-pyridylmethyl 522 965 —H —F —F —H 3-pyridylmethyl 530 966 —H —Cl —H —Cl 3-pyridylmethyl 562 967 —H —CF₃ —H —H 4-pyridylmethyl 562 968 —H —H —Cl —H 3-pyridylmethyl 528 969 —H —CF₃ —H —F 3-pyridylmethyl 580 970 —CH₃ —F —H —H 4-pyridylmethyl 526 971 —H —CH₃ —CH₃ —H 4-pyridylmethyl 522 972 —H —F —F —H 4-pyridylmethyl 530 973 —H —Cl —H —Cl 4-pyridylmethyl 562 974 —H —CF₃ —H —H 4-pyridylmethyl 562 975 —H —H —Cl —H 4-pyridylmethyl 528 976 —H —CF₃ —H —F 4-pyridylmethyl 580 977 —H —OCF₃ —H —H 4-pyridylmethyl 578 978 —CH₃ —F —H —H piperonyl 569 979 —H —CH₃ —CH₃ —H piperonyl 565 980 —H —F —F —H piperonyl 573 981 —H —Cl —H —Cl piperonyl 605 982 —H —CF₃ —H —H piperonyl 605 983 —H —CF₃ —H —F piperonyl 623

Example No. R₇₃₈ 8₇₃₉ 8₇₄₀ R₇₄₁ R₇₄₂ MS (M⁺ + H) 984 —H —OCF₃ —H —H piperonyl 621 985 —H —CH₃ —CH₃ —H benzyl 521 986 —H —F —F —H benzyl 529 987 —CH₃ —F —H —H 4-AcNHPhCH₂— 582 988 —H —CH₃ —CH₃ —H 4-AcNHPhCH₂— 578 989 —H —F —F —H 4-AcNHPhCH₂— 586 990 —H —Cl —H —Cl 4-AcNHPhCH₂— 618 991 —H —CF₃ —H —H 4-AcNHPhCH₂— 618 992 —H —H —Cl —H 4-AcNHPhCH₂— 584 993 —H —CF₃ —H —F 4-AcNHPhCH₂— 636 994 —H —OCF₃ —H —H 4-AcNHPhCH₂— 634 995 —CH₃ —F —H —H 2,3-(CH₃)₂PhCH₂— 553 996 —H —CH₃ —CH₃ —H 2,3-(CH₃)2PhCH₂— 549 997 —H —F —F —H 2,3-(CH₃)₂PhCH₂— 557 998 —H —Cl —H —Cl 2,3-(CH₃)₂PhCH₂— 589 999 —H —CF₃ —H —H 2,3-(CH₃)₂PhCH₂— 589 1000 —H —H —Cl —H 2,3-(CH₃)₂PhCH₂— 555 1001 —H —CF₃ —H —H 2,3-(CH₃)₂PhCH₂— 607 1002 —H —OCF₃ —H —H 2,3-(CH₃)₂PhCH₂— 605 1003 —CH₃ —F —H —H 3-furylmethyl 515 1004 —H —CH₃ —CH₃ —H 3-furylmethyl 511 1005 —H —F —F —H 3-furylmethyl 519 1006 —H —Cl —H —Cl 3-furylmethyl 551 1007 —H —CF₃ —H —H 3-furylmethyl 551 1008 —H —H —Cl —H 3-furylmethyl 517 1009 —H —Cl —Cl —H 3-furylmethyl 551 1010 —H —CF₃ —H —F 3-furylmethyl 569 1011 —H —OCF₃ —H —H 3-furylmethyl 567 1012 —CH₃ —F —H —H 3-pyridyl 512 1013 —H —CH₃ —CH₃ —H 3-pyridyl 508 1014 —H —F —F —H 3-pyridyl 516 1015 —H —Cl —H —Cl 3-pyridyl 548 1016 —H —CF₃ —H —H 3-pyridyl 548 1017 —H —CF₃ —H —F 3-pyridyl 566 1018 —H —OCF₃ —H —H 3-pyridyl 564

TABLE 234

Example No. R₇₄₃ R₇₄₄ R₇₄₅ R₇₄₆ MS (M⁺ + H) 1019 —CH₃ —F —H —H 519 1020 —H —CH₃ —CH₃ —H 515 1021 —H —F —F —H 523 1022 —H —Cl —H —Cl 555 1023 —H —CF₃ —H —H 555 1024 —H —H —Cl —H 521 1025 —H —Cl —Cl —H 555 1026 —H —CF₃ —H —F 573 1027 —H —OCF₃ —H —H 571

TABLE 235

Example No. R₇₄₇ MS (M⁺ + H) 1028 4-CNPhCH₂— 544 1029 2-pyridylmethyl 520 1030 3-pyridylmethyl 520 1031 4-pyridylmethyl 520 1032 4-AcNHPhCH₂— 576 1033 2,3-(CH₃)₂PhCH₂— 547 1034 3-furylmethyl 509 1035

513

Example 1036 Production of 2-{3-methyl-4-[5-(4-trifluoromethylbenzoyl)pyridin-2-yloxy]phenylamino}-1-(4-piperonylpiperazin-1-yl)ethanone

To a solution of 2-chloro-5-(4-trifluoromethylbenzoyl)pyridine (1.00 g, 3.5 mmol) in DMF (30 mL) were added N-(4-hydroxy-3-methylphenyl)glycine ethyl ester (0.81 g, 3.9 mmol), cesium carbonate (1.71 g, 5.2 mmol) and copper (I) iodide (200 mg, 1.05 mmol), and the resulting solution was stirred for 3.5 hours at 60° C. under an argon atmosphere. The resulting reaction solution was filtered and concentrated. To the residue was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 1.20 g of a yellow oil. The yellow oil was dissolved in THF (23 mL), and to the solution was added 1 M aqueous sodium hydroxide (3.9 mL, 3.9 mmol). The resulting solution was stirred for 3 hours at room temperature. This reaction solution was cooled with ice, and made to have a pH of 1 with 6 M hydrochloric acid. The resulting solution was extracted with ethyl acetate, and the ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 1.04 g of a yellow oil. This yellow oil was dissolved in DMF (20 mL), and to the resulting solution were added 1-piperonylpiperazine (530 mg, 2.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (560 mg, 2.9 mmol) and 1-hydroxybenzotriazole monohydrate (390 mg, 2.6 mmol), and the resulting solution was stirred for 15 hours at room temperature. The reaction solution was concentrated under reduced pressure, and to the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2→ethyl acetate), to thereby yield 280 mg of a yellow oil. To this oil was added diethyl ether and left to stand. Precipitated matter was collected by filtration, to thereby yield 220 mg of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 2.11 (3H, s), 2.43-2.48 (4H, m), 3.45-3.48 (4H, m), 3.67-3.71 (2H, m), 3.86 (2H, d, J=4.1 Hz), 4.90 (1H, t, J=4.1 Hz), 5.96 (2H, s), 6.49-6.53 (2H, m), 6.71-6.78 (2H, m), 6.86-6.97 (3H, m), 7.75 (2H, d, J=8.1 Hz), 7.87 (2H, d, J=8.1 Hz), 8.18 (1H, dd, J=8.7 Hz, 2.5 Hz), 8.58 (1H, d, J=2.1 Hz).

The following compound was produced in the same manner as in Example 1036.

Example 1037 6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2,5-difluorophenoxy)-N-(4-trifluoromethylphenyl)nicotinamide hydrobromide

Melting point: 224.5-226.0° C.

Example 1038 Production of N-(6-{2-methyl-4-[methyl-(2-oxo-2-piperazin-1-ylethyl)amino]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide

To a solution of methyl{4-[5-(3,4-dichlorobenzoylamino)-pyridin-2-yloxy]-3-methylphenyl}aminoacetic acid (1.59 g, 3.5 mmol) in DMF (60 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.79 g, 4.1 ml), 1-hydroxybenzotriazole monohydrate (0.63 g, 4.1 mmol), and 1-t-butyloxycarbonylpiperazine (0.68 g, 3.6 mmol). The resulting solution was stirred for 15 hours at room temperature under a nitrogen atmosphere. Water was added to the solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and then the ethyl acetate layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→3:2), to thereby yield an amide product. This amide product was dissolved in THF (20 mL). To the solution was then added 10% hydrochloric acid (10 mL), and the resulting solution was stirred for 14 hours at room temperature. To this reaction solution was added a saturated sodium bicarbonate solution to make the solution neutral, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1→20:1), to thereby yield 0.38 g of the title compound.

Appearance: Colorless amorphous powder

¹H NMR (CDCl₃) δ 2.10 (3H, s), 2.75-2.94 (4H, m), 2.99 (3H, s), 3.40-3.70 (4H, m), 4.08 (2H, s), 6.46-6.59 (2H, m), 6.79 (1H, d, J=8.9 Hz), 6.89 (1H, d, J=8.6 Hz), 7.55 (1H, d, J=8.4 Hz), 7.71 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.98 (1H, d, J=2.1 Hz), 8.03-8.14 (2H, m), 8.23 (1H, d, J=2.6 Hz).

Example 1039 Production of N-(6-{4-[3-(4-piperonylpiperazin-1-yl oxopropyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide

To a solution of 3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propan-1-one trihydrochloride (200 mg, 0.35 mmol) in THF (4 mL) were added triethylamine (0.243 mL, 1.8 mmol) and 4-trifluoromethylbenzoyl chloride (0.055 mL, 0.37 mmol), and the resulting solution was stirred for 1 hour at room temperature. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was recrystallized from diethyl ether, to thereby yield 170 mg of the title compound.

Appearance: White powder

Melting point: 140-141° C.

¹H NMR (CDCl₃) δ 2.32-2.40 (4H, m), 2.59-2.65 (2H, m), 2.93-2.99 (2H, m), 3.41 (4H, brs), 3.60-3.64 (2H, m), 5.94 (2H, s), 6.71-6.77 (2H, m), 6.85 (1H, s), 6.96 (1H, d, J=8.9 Hz), 7.05 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.76 (2H, d, J=8.4 Hz), 8.01 (2H, d, J=8.4 Hz), 8.11-8.14 (1H, m), 8.23 (1H, dd, J=8.9 Hz, 2.7 Hz), 8.28 (1H, d, J=2.7 Hz).

A crude titled product (77.4 g) obtained using the same procedures was recrystallized from ethyl acetate (400 mL), to thereby yield 49.66 g of the title compound.

Appearance: White powder; Melting point: 142-144° C.

The following compounds were produced in the same manner as in Example 1039.

TABLE 236

Example No. Xb₁₁ Xb₁₂ R₇₄₈ mp (°C) or ¹H NMR 1040

—COOC(CH₃)₃ mp 197-199 1041

—OCH₂OCH₃ mp 152-154 1042

—COOC₂H₅ mp 189-190 1043

—N(CH₃)COOC(CH₃)₃ mp 146-147 1044

—COOC(CH₃)₃ mp 192-193 1045

—OCH₂COOC₂H₅ ¹H NMR (CDCl₃) δ 1.30(3H, t, J = 7.0 Hz), 1.75-1.81(2H, m), 2.03(2H, brs), 2.85-2.90(2H, m), 3.45-3.49(2H, m), 3.56(1H, m), 4.15(2H, s), 4.23(2H, q, J = 7.0 Hz), 6.90-6.95(6H, m), 7.50-7.53(3H, m), 7.69(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.95(1H, d, J = 2.0 Hz), 8.04(1H, brs).

TABLE 237

Example No. R₇₄₉ R₇₅₀ R₇₅₁ Xb₁₃ M Form mp (° C.) or ¹H NMR 1046 —Cl —Cl —F —N(Ac)— 1 free ¹H NMR (DMSO-d₆) δ 1.78(3H, s), 2.22-2.38 (4H, m), 3.30- 3.50(6H, m), 4.41(2H, s), 5.98(2H, s), 6.74(1H, d, J = 8.1 Hz), 6.80-6.86(2H, m), 6.98(2H, d, J = 8.8 Hz), 7.29(1H, t, J = 9.2 Hz), 7.38(2H, d, J = 8.8 Hz), 7.58(1H, d, J = 9.2 Hz), 7.84(1H, d, J = 8.4 Hz), 7.90- 7.96(2H, m), 8.21 (1H, d, J = 1.8 Hz), 10.61(1H, s). 1047 —Cl —Cl —F —NH— 0 free mp 224-228 1048 —Cl —Cl —F —NH— 1 dihydrochloride mp 174-1278 1049 —CF₃ —H —H —N(CH₃)— 1 free ¹H NMR (CDCl₃) δ 2.45(4H, brs), 3.03(3H, s), 3.46(2H, s), 3.52(2H, brs), 3.64(2H, brs), 4.08 (2H, s), 5.95(2H, s), 6.67(2H, d, J = 9.1 Hz), 6.74- 6.78(2H, m), 6.87(1H, s), 6.92- 6.97(4H, m), 7.52(2H, d, J = 8.9 Hz), 7.74-7.81(3H, m), 7.98(2H, d, J = 8.2 Hz). 1050 —Cl —Cl —H —N(CH₃)— 1 free ¹H NMR (CDCl₃) δ 2.49(4H, brs), 3.02(3H, s), 3.50(2H, s), 3.55(2H, brs), 3.66(2H, brs), 4.08 (2H, s), 5.96(2H, s), 6.67(2H, d, J = 9.1 Hz), 6.74- 6.78(2H, m), 6.88-6.96(5H, m), 7.50(2H, d, J = 8.9 Hz), 7.56(1H, d, J = 8.4 Hz), 7.70(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.83(1H, s), 7.97(1H, d, J = 2.1 Hz). 1051 —Cl —Cl —F —O— 1 hydrochloride ¹H NMR (DMSO-d₆) δ 2.83- 2.95(1H, m), 2.97-3.12(2H, m), 3.23-3.56(3H, m), 3.95-4.06 (1H, m), 4.18-4.29(2H, m), 4.33- 4.44(1H, m), 4.75-4.92(2H, m), 6.07(2H, s), 6.90-6.96(4H, m), 6.97-7.04(2H, m), 7.11(1H, t, J = 9.1 Hz), 7.15-7.22(1H, m), 7.52(1H, d, J = 9.1 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.88(1H, d, J = 13.3 Hz), 7.94(1H, dd, J = 8.4 Hz, 1.9 Hz), 8.23(1H, d, J = 1.9 Hz), 10.60(1H, s), 11.10(1H, brs).

TABLE 238

Example No. R₇₅₂ R₇₅₃ mp (° C.) or ¹H NMR (CDCl₃) δppm 1052 4-ClPh— benzyl mp 187-190 1053 3-ClPh— benzyl ¹H NMR 2.38(4H, brs), 3.34-3.71(6H, m), 6.86(1H, d, J = 8.8 Hz), 7.00-7.05(2H, m), 7.19-7.36(8H, m), 7.43-7.47(1H, m), 7.69-7.73(1H, m), 7.83(1H, t, J = 1.8 Hz), 8.08(1H, dd, J = 8.8 Hz, 2.8 Hz), 8.24(1H, d, J = 2.6 Hz), 8.51(1H, brs). 1054 4-CH₃Ph— 4-CH₃OPhCH₂— ¹H NMR 2.32-2.50(7H, m), 3.44-3.79(9H, m), 6.84- 6.92(3H, m), 7.06-7.11(2H, m), 7.20-7.23(4H, m), 7.34-7.39(2H, m), 7.79(2H, d, J = 8.3 Hz), 8.16- 8.21(1H, m), 8.35(1H, d, J = 2.8 Hz), 8.76(1H, brs). 1055 2-naphthyl 4-CH₃OPhCH₂— ¹H NMR 2.41(4H, brs), 3.46-3.80(6H, m), 3.81(3H, s), 6.83-6.90(2H, m), 6.95(1H, d, J = 8.7 Hz), 7.10(2H, d, J = 8.7 Hz), 7.22(2H, d, J = 8.6 Hz), 7.38(2H, d, J = 8.7 Hz), 7.52-7.63 (2H, m), 7.88- 7.97(4H, m), 8.27(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.41-8.43(2H, m), 8.80(1H, brs). 1056 4-ClPh— 4-CH₃OPhCH₂— ¹H NMR 2.43(4H, brs), 3.48-3.77(6H, m), 3.80(3H, s), 6.83-6.89(2H, m), 6.96(1H, d, J = 8.9 Hz), 7.10- 7.15(2H, m), 7.22(2H, d, J = 8.6 Hz), 7.38-7.48(4H, m), 7.82-7.87(2H, m), 8.17-8.21(2H, m), 8.30(1H, d, J = 2.6 Hz). 1057 3-ClPh— 4-CH₃OPhCH₂— ¹H NMR 2.41(4H, brs), 3.46-3.76(6H, m), 3.79(3H, s), 6.83-6.89(3H, m), 7.05(2H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.31-7.48(4H, m), 7.77(1H, d, J = 7.8 Hz), 7.90(1H, s), 8.08-8.12(1H, m), 8.35(1H, d, J = 2.5 Hz), 9.26(1H, brs). 1058 4-CF₃OPh— benzyl mp 152-153 1059 2,4-Cl₂Ph— benzyl mp 196-197 1060 2,3-F₂Ph— benzyl mp 172-175 1061 4-ClPh— piperonyl ¹H NMR 2.45(4H, brs), 3.45(2H, s), 3.45-3.75(4H, m), 5.95(2H, s), 6.74-6.77(2H, m), 6.86(1H, s), 6.99(1H, d, J = 8.9 Hz), 7.14 (2H, d, J = 8.7 Hz), 7.42-7.51(4H, m), 7.84(2H, d, J = 8.7 Hz), 7.91(1H, brs), 8.22(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.29(1H, d, J = 2.1 Hz) 1062 4-ClPh— 3-pyridyl ¹H NMR 3.24(4H, brs), 3.49-3.82(4H, m), 7.02(1H, d, J = 8.7 Hz), 7.16-7.24(4H, m), 7.48(2H, d, J = 8.9 Hz), 7.49(2H, d, J = 8.7 Hz), 7.85(2H, d, J = 8.7 Hz), 8.04(1H, brs), 8.15-8.17(1H, m), 8.24(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.31-8.32(2H, m).

TABLE 239

Example No. R₇₅₄ R₇₅₅ Xb₁₄ Form Property 1063 3-CF₃OPh— benzyl —CO— maleate mp 155-157° C. 1064 3,5-Cl₂Ph— benzyl —CO— dihydrochloride ¹H NMR (DMSO-d₆) δ 3.15- 3.54(8H, m), 4.36(2H, s), 7.15-7.22(3H, m), 7.47- 7.60(7H, m), 7.90-7.91(1H, m), 8.00(1H, s), 8.01(1H, s), 8.22-8.27(1H, m), 8.54(1H, d, J = 2.2 Hz), 10.69(1H, s). 1065 PhCH═CH-(trans) benzyl —CO— free MS 518(M⁺) 1066 PhCH═CH-(trans) piperonyl —CO— free ¹H NMR (CDCl₃) δ 2.45(4H, brs), 3.44 (2H, s), 3.52(2H, brs), 3.76(2H, brs), 5.95 (2H, s), 6.60(1H, d, J = 15.5 Hz), 6.74-6.77(2H, m), 6.85(1H, s), 6.95(1H, d, J = 8.7 Hz), 7.12(2H, d, J = 8.6 Hz), 7.38-7.45(5H, m), 7.53- 7.56(2H, m), 7.74 (1H, brs), 7.77(1H, d, J = 15.5 Hz), 8.21 (1H, d, J = 8.4 Hz), 8.25(1H, d, J = 2.5Hz). 1067 PhCH═CH-(trans) 3-pyridyl —CO— free ¹H NMR (CDCl₃) δ 3.20(4H, brs), 3.79 (4H, brs), 6.67(1H, d, J = 15.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 7.10-7.21(4H, m), 7.33- 7.46(7H, m), 7.73(1H, d, J = 15.7 Hz), 8.11-8.31(4H, m), 9.30(1H, s). 1068 3,4-Cl₂Ph— benzyl —SO₂— hydrochloride mp 253-256° C. 1069 4-CF₃Ph— benzyl —SO₂— hydrochloride mp 249-251° C.

TABLE 240

Example No. R₇₅₆ R₇₅₇ Xb₁₅ M ¹H NMR (solvent) δppm 1070 3,4-Cl₂Ph— benzyl —CH(OH)— 0 (CDCl₃) 1.95-2.15(1H, m), 2.15-2.40(3H, m), 3.42 (2H, s), 3.49(4H, brs), 5.42(1H, d, J = 6.6 Hz), 5.61 (1H, d, J = 6.6 Hz), 7.08(1H, d, J = 8.9 Hz), 7.09(2H, d, J = 8.6 Hz), 7.15-7.43(5H, m), 7.38(2H, d, J = 8.6 Hz), 7.85(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.20(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.23(1H, d, J = 2.3 Hz), 8.50(1H, d, J = 2.7 Hz), 10.57(1H, s). 1071 4-CF₃Ph— benzyl —CH(OH)— 0 (CDCl₃) 1.90-2.05(1H, m), 2.22-2.57(3H, m), 3.10-3.40(2H, m), 3.44(2H, s), 3.58- 3.85(2H, m), 4.75(1H, d, J = 6.4 Hz), 5.21(1H, d, J = 6.4 Hz), 6.96 (1H, d, J = 8.9 Hz), 7.12(2H, d, J = 8.6 Hz), 7.20-7.38 (5H, m), 7.32(2H, d, J = 8.6 Hz), 7.78(2H, d, J = 8.1 Hz), 7.92(1H, brs), 8.00(2H, d, J = 8.1 Hz), 8.22(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.29(1H, d, J = 2.5 Hz). 1072 4-CF₃Ph— piperonyl —O— 1 (DMSO-d₆) 2.32(2H, brs), 2.40(2H, brs), 3.41(2H, s), 3.46(4H, brs), 4.81(2H, s), 5.99(2H, s), 6.73-6.88(3H, m), 6.94(2H, d, J = 9.2 Hz), 7.02(1H, d, J = 8.7 Hz), 7.05(2H, d, J = 9.2 Hz), 7.93(2H, d, J = 8.4 Hz), 8.16 (2H, d, J = 8.4 Hz), 8.19(1H, dd, J = 8.7 Hz, 2.7 Hz), 8.47(1H, d, J = 2.7 Hz), 10.60(1H, s). 1073 4-CF₃Ph— benzyl —O— 1 (CDCl₃) 2.35-2.53(4H, m), 3.51(2H, s), 3.56(2H, t, J = 5.0 Hz), 3.62(2H, t, J = 5.0 Hz), 4.64(2H, s), 6.90 (1H, d, J = 8.8 Hz), 6.92(2H, d, J = 9.0 Hz), 7.04(2H, d, J = 9.0 Hz), 7.21-7.41(5H, m), 7.73(2H, d, J = 8.1 Hz), 8.00(2H, d, J = 8.1 Hz), 8.18(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.27(1H, d, J = 2.6 Hz), 8.32(1H, brs). 1074 3-ClPh— piperonyl none 2 (CDCl₃) 2.31-2.38(4H, m), 2.58-2.64(2H, m), 2.90-2.96(2H, m), 3.37-3.40(4H, m), 3.59-3.62(2H, m), 5.94(2H, s), 6.70- 6.77(2H, m), 6.84(1H, s), 6.92 (1H, d, J = 8.9 Hz), 7.03(2H, d, J = 8.4 Hz), 7.20(2H, d, J = 8.4 Hz), 7.38-7.44(1H, m), 7.50- 7.54(1H, m), 7.77(1H, d, J = 7.8 Hz), 7.87- 7.88(1H, m), 8.21(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.28(1H, d, J = 2.7 Hz), 8.36 (1H, s).

TABLE 241

Example No. R₇₅₈ mp (° C.) or ¹H NMR 1075 3-ClPh— ¹H NMR (CDCl₃) δ 2.33-2.38(4H, m), 2.55-2.61(2H, m), 2.86- 2.91(2H, m), 3.37-3.41(2H, m), 3.49(2H, s), 3.56-3.60(2H, m), 6.87(1H, d, J = 8.9 Hz), 6.97-7.01(2H, m), 7.14(2H, d, J = 8.6 Hz), 7.25-7.37(6H, m), 7.45-7.48(1H, m), 7.75-7.79(1H, m), 7.87(1H, t, J = 1.8 Hz), 8.18(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.32 (1H, d, J = 2.8 Hz), 9.06(1H, brs). 1076 4-ClPh— mp 136-139 1077 2-ClPh— ¹H NMR (CDCl₃) δ 2.32-2.41(4H, m), 2.56-2.61(2H, m), 2.90- 2.96(2H, m), 3.37-3.41(2H, m), 3.50(2H, s), 3.58-3.61(2H, m), 6.92(1H, d, J = 8.7 Hz), 7.03 (2H, d, J = 8.4 Hz), 7.19-7.43(10H, m), 7.69-7.72(1H, m), 8.21-8.27(3H, m). 1078 Ph— ¹H NMR (CDCl₃) δ 2.36(4H, brs), 2.56-2.61(2H, m), 2.89-2.95(2H, m), 3.36-3.41(2H, m), 3.49(2H, s), 3.58-3.62(2H, m), 6.99(1H, d, J = 8.7 Hz), 7.01 (2H, d, J = 8.1 Hz), 7.18(2H, d, J = 8.1 Hz), 7.26- 7.55(8H, m), 7.87(2H, d, J = 6.6 Hz), 8.20(1H, d, J = 8.7 Hz), 8.28(1H, brs), 8.50(1H, brs). 1079 4-CNPh— ¹H NMR (CDCl₃) δ 2.33-2.41(4H, m), 2.56-2.62(2H, m), 2.87- 2.92(2H, m), 3.38-3.42(2H, m), 3.50(2H, s), 3.56-3.60(2H, m), 6.91(1H, d, J = 8.9 Hz). 6.98-7.01(2H, m), 7.14-7.19(2H, m), 7.25- 7.35(5H, m), 7.71-7.75(2H, m), 7.99-8.02(2H, m), 8.17-8.29(2H, m), 8.75-8.97(1H, m). 1080 3-CH₃OPh— ¹H NMR (CDCl₃) δ 2.33-2.41(4H, m), 2.56-2.62(2H, m), 2.90- 2.95(2H, m), 3.38-3.42(2H, m), 3.51(2H, s), 3.60-3.63(2H, m), 3.83(3H, s), 6.90(1H, d, J = 8.7 Hz), 7.00-7.09(3H, m), 7.18(2H, d, J = 8.6 Hz), 7.26-7.44(8H, m), 8.19-8.23(1H, m), 8.29(1H, d, J = 2.8 Hz), 8.48(1H, brs). 1081 4-CH₃Ph— ¹H NMR (CDCl₃) δ 2.33-2.40(7H, m), 2.56-2.62(2H, m), 2.90 2.95(2H, m), 3.38-3.41(2H, m), 3.49(2H, s), 3.59-3.62(2H, m), 6.89(1H, d. J = 8.7 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.16-7.32(9H, m), 7.78(2H, d, J = 8.2 Hz), 8.18-8.22(1H, m), 8.27(1H, d, J = 2.6 Hz), 8.33-8.44(1H, m). 1082 2-CH₃Ph— ¹H NMR (CDCl₃) δ 2.32-2.40(4H, m), 2.48(3H, s), 2.55-2.60(2H, m), 2.89-2.95 (2H, m), 3.37-3.40(2H, m), 3.50(2H, s), 3.57-3.60(2H, m), 6.89-6.92(1H, m), 7.00-7.05(2H, m), 7.18-7.47(10H, m), 7.45(1H, d, J = 2.2 Hz), 8.04(1H, brs), 8.23-8.25(2H, m). 1083 4-CH₃OPh— ¹H NMR (CDCl₃) δ 2.31-2.38(4H, m), 2.54-2.60(2H, m), 2.87- 2.93(2H, m), 3.37-3.40(2H, m), 3.48(2H, s), 3.58-3.61(2H, m), 3.82(3H, s), 6.84-6.90(3H, m), 6.99(2H, d, J = 8.4 Hz), 7.15(2H, d, J = 8.6 Hz), 7.25-7.32(5H, m), 7.85(2H, d, J = 8.9 Hz), 8.17(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.28(1H, d, J = 2.7 Hz). 8.73(1H, brs). 1084 2-CH₃OPh— ¹H NMR (CDCl₃) δ 2.33-2.42(4H, m), 2.58-2.64(2H, m), 2.93- 2.99(2H, m), 3.38-3.42(2H, m), 3.49(2H, s), 3.61-3.65(2H, m), 4.02(3H, s), 6.89-6.92(1H, m), 7.01-7.32(11H, m), 7.47-7.53(1H, m), 8.23-8.29(3H, m), 9.76(1H, s). 1085 2-naphthyl mp 156-159 1086 4-CF₃Ph— ¹H NMR (DMSO-d₆) δ 2.30-2.32(4H, m), 2.59-2.65(2H, m), 2.79- 2.84(2H, m), 3.44-3.47(6H, m), 7.02(2H, d, J = 8.6 Hz), 7.05(1H, d, J = 9.1 Hz), 7.25-7.35(7H, m), 7.93(2H, d, J = 8.3 Hz), 8.16(2H, d, J = 8.3 Hz), 8.21(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.49(1H, d, J = 2.6 Hz). 10.62(1H, brs).

TABLE 242

Example No. R₇₅₉ R₇₆₀ Form mp (° C.) or ¹H NMR 1087 4-CF₃OPh— benzyl maleate mp 144-146 1088 3-CF₃OPh— benzyl maleate mp 125-128 1089 4-CF₃OPh— piperonyl free mp 187-190 1090 2-CF₃OPh— piperonyl free ¹H NMR (CDCl₃) δ 2.31-2.39(4H, m), 2.57- 2.63(2H, m), 2.91-2.97(2H, m), 3.37- 3.40(4H, m), 3.58-3.62(2H, m), 5.93(2H, s), 6.70-6.76(2H, m), 6.84(1H, s), 6.93(1H, d, J = 8.9 Hz), 7.03-7.07(2H, m), 7.19-7.23(2H, m), 7.32-7.36(1H, m), 7.40-7.46(1H, m), 7.53-7.59(1H, m), 7.99-8.03(1H, m), 8.20(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.27 (1H, d, J = 2.7 Hz), 8.55(1H, brs). 1091 3-CF₃OPh— piperonyl free ¹H NMR (CDCl₃) δ 2.30-2.36(4H, m), 2.55- 2.61(2H, m), 2.86-2.92(2H, m), 3.37- 3.40(4H, m), 3.56-3.60(2H, m), 5.93(2H, s), 6.69-6.76(2H, m), 6.83(1H, s), 6.88-6.92 (1H, m), 6.98-7.02(2H, m), 7.14-7.18(2H, m), 7.36-7.40 (1H, m), 7.44-7.52(1H, m), 7.78- 7.85(2H, m), 8.19(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.29-8.31(1H, m), 8.78-8.92(1H, m). 1092 3,5-Cl₂Ph— piperonyl dihydrochloride ¹H NMR (DMSO-d₆) δ 2.69-3.33(10H, m), 3.99-4.11 (1H, m), 4.23(2H, s), 4.44-4.49(1H, m), 6.07(2H, s), 6.97-7.07(5H, m), 7.20- 7.30(3H, m), 7.89-8.00(1H, m), 8.00(2H, d, J = 1.8 Hz), 8.19(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.48(1H, d, J = 2.3 Hz), 10.64(1H, s). 1093 PhCH═CH-(trans) piperonyl free ¹H NMR (CDCl₃) δ 2.05-3.38(9H, m), 3.69- 4.71(5H, m), 5.96(2H, s), 6.72-6.79(2H, m), 6.95-7.05(4H, m), 7.13-7.23(3H, m), 7.35- 7.37(3H, m), 7.51-7.54(2H, m), 7.70- 7.76(1H, m), 8.41(1H, d, J = 2.3 Hz), 8.50(1H, d, J = 8.7 Hz), 8.95(1H, brs). 1094 2-naphthyl piperonyl free ¹H NMR (CDCl₃) δ 2.28-2.34(4H, m), 2.55- 2.61(2H, m), 2.89-2.95(2H, m), 3.38(4H, brs), 3.58(2H, brs), 5.92 (2H, s), 6.69- 6.76(2H, m), 6.83(1H, s), 6.92(1H, d, J = 8.6 Hz), 7.02(2H, d, J = 8.4 Hz), 7.18(2H, d, J = 8.4 Hz), 7.51-7.61(2H, m), 7.86-7.94(4H, m), 8.27(1H, dd, J = 8.6 Hz, 2.7 Hz), 8.33- 8.38(2H, m), 8.55(1H, brs). 1095 4-ClPh— piperonyl free ¹H NMR (CDCl₃) δ 2.31-2.41(4H, m), 2.59- 2.65(2H, m), 2.94-3.00(2H, m), 3.38- 3.41(4H, m), 3.63(2H, brs), 5.94(2H, s), 6.71- 6.77(2H, m), 6.85(1H, s), 6.95(1H, d, J = 8.9 Hz), 7.05(2H, d, J = 8.4 Hz), 7.23(2H, d, J = 8.4 Hz), 7.48(2H, d, J = 8.6 Hz), 7.82- 7.89(3H, m), 8.19-8.25 (2H, m).

TABLE 243

Example No. R₇₆₁ R₇₆₂ R₇₆₃ R₇₆₄ R₇₆₅ ¹H NMR (CDCl₃) δppm 1096 4-CF₃Ph— —H —H —OH —COOC(CH₃)₃ 1.44(9H, s), 2.82-3.00(2H, m), 3.00-3.80 (9H, m), 4.60(1H, t, J = 6.5 Hz), 6.97(1H, d, J = 8.8 Hz), 7.06(2H, d, J = 8.6 Hz), 7.24 (2H, d, J = 8.6 Hz), 7.75(2H, d, J = 8.1 Hz), 8.00(2H, d, J = 8.1 Hz), 8.07(1H, brs), 8.18 (1H, d, J = 2.6 Hz), 8.27(1H, dd, J = 8.8 Hz, 2.6 Hz). 1097 4-CF₃Ph— —H —CH₃ —H piperonyl 2.32(3H, s), 2.32-2.40(4H, m), 2.59-2.64 (2H, m), 2.93-2.98(2H, m), 3.30-3.45(4H, m), 3.55- 3.70(2H, m), 5.94(2H, s), 6.65- 6.75(2H, m), 6.82-6.84(2H, m), 7.03-7.07(2H, m), 7.20-7.24(2H, m), 7.72(1H, brs), 7.75-7.79(2H, m), 8.00-8.04(2H, m), 8.30(1H, s). 1098 4-CF₃Ph— —CH₃ —H —H piperonyl 2.31-2.40(4H, m), 2.47(3H, s), 2.59-2.65(2H, m), 2.94-3.00(2H, m), 3.38-3.41(4H, m), 3.60- 3.65(2H, m), 5.94(2H, s), 6.68- 6.77(3H, m), 6.84(1H, s), 7.04- 7.08(2H, m), 7.20-7.24(2H, m), 7.63(1H, brs), 7.77-7.80(2H, m), 7.99-8.11(3H, m). 1099 3,4-Cl₂Ph— —CH₃ —H —H piperonyl 2.25-2.40(4H, m), 2.45(3H, s), 2.58-2.64(2H, m), 2.92-2.98(2H, m), 3.38-3.41(4H, m), 3.60- 3.64(2H, m), 5.94(2H, s), 6.66- 6.76(3H, m), 6.84(1H, s), 7.03- 7.07(2H, m), 7.18-7.22(2H, m), 7.59(1H, d, J = 8.3 Hz), 7.67(1H, brs), 7.72(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.98-8.02(2H, m). 1100 3,4-Cl₂Ph— —H —CH₃ —H piperonyl 2.31(3H, s), 2.31-2.40(4H, m), 2.58-2.64(2H, m), 2.92-2.98(2H, m), 3.37-3.41(4H, m), 3.60- 3.64(2H, m), 5.94(2H, s), 6.65- 6.75(2H, m), 6.80-6.84(2H, m), 7.03-7.06(2H, m), 7.20-7.24(2H, m), 7.58(1H, d, J = 8.3 Hz), 7.64(1H, brs), 7.73(1H, dd, J = 8.3 Hz, 1.8 Hz), 8.01(1H, d, J = 1.9 Hz), 8.26(1H, s).

TABLE 244

Example No. R₇₆₆ R₇₆₇ R₇₆₈ R₇₆₉ mp (° C.) or ¹H NMR (solvent) δppm 1101 4-CF₃Ph— —H —H —Ac mp 189-191 1102 3,4-Cl₂Ph— —H —H —COC₂H₅ mp 204-206 1103 3,4-Cl₂Ph— —H —H —H mp 188-189 1104 3,4-Cl₂Ph— —H —H

¹H NMR (DMSO-d₆) 0.60-0.70(2H, m), 0.75- 0.80 (2H, m), 1.42(1H, m), 2.25-2.35(4H, m), 3.35-3.45(6H, m), 4.49(2H, s), 5.98(2H, s), 6.74(1H, d, J = 7.9 Hz), 6.84(1H, d, J = 7.9 Hz), 6.86(1H, s), 7.12(1H, d, J = 8.8 Hz), 7.18(2H, d, J = 8.6 Hz), 7.47(2H, d, J = 8.6 Hz), 7.84(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.20-8.23(2H, m), 8.51(1H, d, J = 2.5 Hz), 10.58(1H, s). 1105 4-CF₃Ph— —H —H —CH₃ H NMR (DMSO-d₆) 2.31-2.39(4H, m), 2.94(3H, s), 3.31(2H, s), 3.42(4H, brs), 4.24(2H, s), 5.99(2H, s), 6.64 (2H, d, J = 9.1 Hz), 6.76(1H, dd, J = 7.9 Hz, 1.2 Hz), 6.84- 6.96(5H, m), 7.93(2H, d, J = 8.3 Hz), 8.13(1H, s), 8.16(2H, d, J = 8.6 Hz), 8.45(1H, d, J = 2.5 Hz), 10.58(1H, s). 1106 3,4-Cl₂Ph— —H —H

¹H NMR (CDCl₃) 0.57-0.62(2H, m), 0.75- 0.82(2H, m), 2.37-2.49(4H, m), 2.70-2.74(1H, m), 3.45(2H, s), 3.49-3.59(4H, m), 4.17(2H, s), 5.95(2H, s), 6.74-6.94 (8H, m), 7.49(1H, d, J = 8.2 Hz), 7.67-7.71(1H, m), 7.95 (1H, d, J = 2.1 Hz), 8.00(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24 (1H, d, J = 2.6 Hz), 8.59(1H, brs). 1107 4-CF₃Ph— —H —H

¹H NMR (CDCl₃) 0.57-0.62(2H, m), 0.74- 0.81(2H, m), 2.35-2.47(4H, m), 2.66-2.74(1H, m), 3.44(2H, s), 3.47-3.57(4H, m), 4.16(2H, s), 5.94(2H, s), 6.70-6.94 (8H, m), 7.66(2H, d, J = 8.2 Hz), 7.95(2H, d, J = 8.0 Hz), 8.04(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.6 Hz), 8.80(1H, s). 1108 4-CF₃Ph— —CH₃ —CH₃ —CH₃ ¹H NMR (CDCl₃) 2.09(3H, s), 2.26(3H, s), 2.39(4H, brs), 2.67(3H, s), 3.41(2H, s), 3.53- 3.63(4H, m), 3.74(2H, s), 5.94(2H, s), 6.71- 6.77(2H, m), 6.85-6.90(3H, m), 6.98 (1H, d, J = 8.7 Hz), 7.75(2H, d, J = 8.2 Hz), 7.98-8.01 (3H, m), 8.18(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.25(1H, d, J = 2.3 Hz). 1109 3,4-Cl₂Ph— —CH₃ —CH₃ —CH₃ ¹H NMR (CDCl₃) 2.09(3H, s), 2.25(3H, s), 2.37-2.40 (4H, m), 2.66(3H, s), 3.41(2H, s), 3.53-3.63(4H, m), 3.73 (2H, s), 5.94(2H, s), 6.70-6.77(2H, m), 6.84-6.89(3H, m), 6.96(1H, d, J = 8.7 Hz), 7.56(1H, d, J = 8.2 Hz), 7.70- 7.74(1H, m), 7.99(1H, d, J = 2.0 Hz), 8.10- 8.16(2H, m), 8.24(1H, d, J = 2.8 Hz).

TABLE 245

Example No. R₇₇₀ R₇₇₁ R₇₇₂ Form mp (° C.) or ¹H NMR (solvent) δppm 1110 4-CF₃Ph— —OCH₃ —C₂H₅ free mp 142.6-146.5 1111 4-CF₃Ph— —CH₃ —C₂H₅ hydrochloride mp 173-175 dec 1112 3,4-Cl₂Ph— —CH₃ —C₂H₅ hydrochloride mp 168.5-171.0 1113 2,3-Cl₂Ph— —CH₃ —CH₃ free ¹H NMR (CDCl₃) 2.12(3H, s), 2.41-2.45(4H, m), 3.01(3H, s), 3.43(2H, s), 3.50(2H, brs), 3.63(2H, brs), 4.07(2H, s), 5.95(2H, s), 6.52- 6.58(2H, m), 6.71-6.77 (2H, m), 6.81- 6.93(3H, m), 7.32(1H, t, J = 7.8 Hz), 7.56- 7.61(2H, m), 7.68(1H, brs), 8.16(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.20(1H, d, J = 2.2 Hz). 1114 3,4-Cl₂Ph— —OCH₃ —H free ¹H NMR (DMSO-d₆) 2.32-2.40(4H, m), 3.42(2H, s), 3.51(4H, brs), 3.63(3H, s), 3.91(2H, d, J = 4.8 Hz), 5.54 (1H, t, J = 4.8 Hz), 5.99(2H, s), 6.21(1H, dd, J = 8.6 Hz, 2.5 Hz), 6.50(1H, d, J = 2.5 Hz), 6.76(1H, dd, J = 7.9 Hz, 1.5 Hz), 6.82-6.88(4H, m), 7.82(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.07(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.21(1H, d, J = 2.2 Hz), 8.37(1H, d, J = 2.5 Hz), 10.44(1H, s). 1115 4-CF₃Ph— —OCH₃ —H free ¹H NMR (CDCl₃) 2.32-2.40(4H, m), 3.42(2H, s), 3.50(4H, brs), 3.63(3H, s), 3.91(2H, d, J = 4.6 Hz), 5.55 (1H, brt), 5.99(2H, s), 6.20(1H, dd, J = 8.6 Hz, 2.5 Hz), 6.49(1H, d, J = 2.3 Hz), 6.74-6.88(5H, m), 7.92(2H, d, J = 8.4 Hz), 8.07-8.17(3H, m), 8.38(1H, d, J = 2.3 Hz), 10.53(1H, s). 1116 4-CF₃Ph— —CH₃

free ¹H NMR (CDCl₃) 0.59-0.64(2H, m), 0.76- 0.82(2H, m), 2.08(3H, s), 2.37-2.47(4H, m), 2.69-2.77(1H, m), 3.44 (2H, s), 3.48-3.59(4H, m), 4.16(2H, s), 5.94(2H, s), 6.67-6.77(5H, m), 6.86(2H, d, J = 8.6 Hz), 7.70(2H, d, J = 8.2 Hz), 7.97(2H, d, J = 8.1 Hz), 8.08(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.23(1H, d, J = 2.8 Hz), 8.39(1H, brs). 1117 3,4-Cl₂Ph— —CH₃

free ¹H NMR (CDCl₃) 0.59-0.65(2H, m), 0.76- 0.83(2H, m), 2.08(3H, s), 2.38-2.48(4H, m), 2.71-2.78(1H, m), 3.44(2H, s), 3.49-3.59 (4H, m), 4.17(2H, s), 5.95(2H, s), 6.67-6.77 (5H, m), 6.85-6.88(2H, m), 7.53(1H, d, J = 8.2 Hz), 7.68-7.72(1H, m), 7.96(1H, d, J = 2.0 Hz), 8.02-8.07(1H, m), 8.22-8.26(2H, m). 1118

—CH₃ —CH₃ free ¹H NMR (CDCl₃) 0.83-0.85(2H, m), 1.07- 1.08(2H, m), 1.46-1.63(1H, m), 2.10(3H, s), 2.41-2.44(4H, m), 3.00(3H, s), 3.43(2H, s), 3.47-3.49(2H, m), 3.63(2H, brs), 4.06(2H, s), 5.94(2H, s), 6.51-6.55(2H, m), 6.70-6.77(3H, m), 6.85(1H, brs), 6.89(1H, d, J = 8.4 Hz), 7.44-7.64(1H, m), 8.01-8.04(1H, m), 8.08(1H, d, J = 2.3 Hz).

TABLE 246

Example No. R₇₇₃ R₇₇₄ R₇₇₅ Form ¹H NMR (solvent) δppm 1119

—CH₃ —CH₃ hydrochloride (DMSO-d₆) 2.01(3H, s), 2.80-3.18(3H, m), 2.93 (3H, s), 3.35(2H, s), 3.38- 3.62(1H, m), 3.95-4.50 (4H, m), 4.27(2H, s), 6.08(2H, s), 6.49(1H, dd, J = 8.7 Hz, 2.7 Hz), 6.58(1H, d, J = 2.7 Hz), 6.83(1H, d, J = 8.7 Hz), 6.92(1H, d, J = 8.9 Hz), 7.02(2H, s), 7.21(1H, s), 7.74(1H, d, J = 8.4 Hz), 7.90(1H, d, J = 8.4 Hz), 7.88-7.95(1H, m), 8.11(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.36(1H, d, J = 2.7 Hz), 10.71(1H, s). 1120

—CH₃ —CH₃ free (CDCl₃) 2.11(3H, s), 2.42(4H, brs), 3.00(3H, s), 3.43(2H, s), 3.47-3.49(2H, m), 3.63(2H, brs), 4.07(2H, s), 5.95(2H, s), 6.01(2H, s), 6.37(1H, d, J = 15.2 Hz), 6.52-6.56(2H, m), 6.74-6.85(5H, m), 6.91(1H, d, J = 8.6 Hz), 7.00- 7.02(2H, m), 7.49(1H, brs), 7.65(1H, d, J = 15.3 Hz), 8.16-8.17(2H, m). 1121

—CH₃ —CH₃ free (CDCl₃) 2.09(3H, s), 2.42-2.43(4H, m), 3.00(3H, s), 3.43(2H, s), 3.47-3.50(2H, m), 3.63(2H, brs), 4.08(2H, s), 5.95(2H, s), 6.49-6.61(3H, m), 6.70-6.91(6H, m), 7.01-7.03(2H, m), 7.63(1H, d, J = 15.3 Hz), 7.93(1H, brs), 8.16-8.19(2H, m). 1122

—CH₃ —CH₃ free (CDCl₃) 2.17(3H, s), 2.43(4H, brs), 2.82(3H, s), 3.01(3H, s), 3.44(2H, s), 3.50(2H, brs), 3.63(2H, brs), 4.08(2H, s), 5.95(2H, s), 6.53-6.57(2H, m), 6.74(2H, brs), 6.81(1H, d, J = 8.9 Hz), 6.85(1H, s), 6.92(1H, d, J = 8.6 Hz), 7.52(1H, brs), 7.73 (2H, d, J = 8.3 Hz), 8.04-8.09(3H, m), 8.18(1H, d, J = 2.8 Hz). 1123 4-CF₃Ph— —F allyl free (CDCl₃) 2.45(4H, brs), 3.45(2H, s), 3.45(2H, brs), 3.64(2H, brs), 3.99(2H, d, J = 5.1 Hz), 4.05 (2H, s), 5.18- 5.28(2H, m), 5.83-5.93(1H, m), 5.95(2H, s), 6.36-6.47(2H, m), 6.75(2H, s), 6.86-6.87(1H, m), 6.96(1H, d, J = 9.1 Hz), 7.03 (1H, t, J = 8.9 Hz), 7.75- 7.78(3H, m), 7.99(2H, d, J = 8.1 Hz), 8.15-8.22(2H, m). 1124

—CH₃ —CH₃ free (CDCl₃) 0.83-0.87(1H, m), 1.19- 1.22(7H, m), 1.37-1.42(1H, m), 2.10(3H, s), 2.41-2.44(4H, m), 3.00(3H, s), 3.43(2H, s), 3.48(2H, brs), 3.63(2H, brs), 4.06(2H, s), 5.94(2H, s), 6.51- 6.56(2H, m), 6.70-6.77(3H, m), 6.85- 6.91(2H, m), 7.40(1H, brs), 8.05- 8.06(2H, m).

TABLE 247

Example No. R₇₇₆ R₇₇₇ R₇₇₈ R₇₇₉ M mp (° C.) or ¹H NMR 1125 4-CF₃Ph— —F —F —CH₃ 1 mp 160.0-161.5 1126 3,4-Cl₂Ph— —F —F —CH₃ 1 mp 207-209 1127 4-CF₃Ph— —F —F —C₂H₅ 1 ¹H NMR (DMSO-d₆) δ 1.07(3H, t, J = 7.0 Hz), 2.20-2.41(4H, m), 3.20-3.30(2H, m), 3.39(2H, s), 3.39-3.52(4H, m), 4.11(2H, s), 5.97(2H, s), 6.71-6.76(1H, m), 6.78- 6.88(3H, m), 7.09-7.19 (2H, m), 7.92(2H, d, J = 8.4 Hz), 8.15(2H, d, J = 8.4 Hz), 8.20(1H, dd, J = 2.7 Hz, 9.0 Hz), 8.42 (1H, d, J = 2.7 Hz). 1128 3,4-Cl₂Ph— —CH₃ —CH₃ —C₂H₅ 1 ¹H NMR (DMSO-d₆) δ 0.95(3H, t, J = 7.0 Hz), 2.01(3H, s), 2.19(3H, s), 2.20- 2.40(4H, m), 3.00 (2H, q, J = 7.0 Hz), 3.30-3.55(6H, m), 3.79(2H, s), 5.98(2H, s), 6.74(1H, dd, J = 7.9 Hz, 1.4 Hz), 6.82-6.86 (3H, m), 6.97(1H, d, J = 8.9 Hz), 7.05 (1H, s), 7.84(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.21(1H, d, J = 2.0 Hz), 8.42(1H, d, J = 2.6 Hz), 10.51(1H, brs). 1129 4-CF₃Ph— —CH₃ —CH₃ —C₂H₅ 1 ¹H NMR (DMSO-d₆) δ 0.95(3H, t, J = 7.0 Hz), 2.02(3H, s), 2.19(3H, s), 2.20- 2.40(4H, m), 3.00 (2H, q, J = 7.0 Hz), 3.30-3.60(6H, m), 3.79(2H, s), 5.98(2H, s), 6.74(1H, d, J = 7.9 Hz), 6.82-6.85(3H, m), 6.98(1H, d, J = 8.6 Hz), 7.05(1H, s), 7.91- 7.95(2H, m), 8.14-8.20(3H, m), 8.44(1H, d, J = 1.8 Hz), 10.59(1H, brs). 1130 4-CF₃Ph— —OCH₃ —H —H 2 ¹H NMR (CDCl₃) δ2.44(4H, brs), 3.43(4H, brs), 3.49(2H, s), 3.66(3H, s), 3.83(2H, brs), 4.25(4H, s), 4.67(1H, brs), 6.10(1H, dd, J = 8.6 Hz, 2.5 Hz), 6.23(1H, d, J = 2.5 Hz), 6.75-6.96(5H, m), 7.67(2H, d, J = 8.3 Hz), 7.96(2H, d, J = 8.1 Hz), 8.10(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.20-8.24(1H, m), 8.56(1H, s).

TABLE 248

Example No. R₇₈₀ R₇₈₁ R₇₈₂ R₇₈₃ mp (° C.) or ¹H NMR (solvent) δppm 1131

—CH₃ —H —H ¹H NMR (CDCl₃) 2.13(3H, s), 2.43(4H, t, J = 4.8 Hz), 3.02 (3H, s), 3.44(2H, s), 3.50(2H, brs), 3.64(2H, brs), 4.08(2H, s), 5.94(2H, s), 6.53-6.58(2H, m), 6.74(2H, brs), 6.83(1H, d, J = 8.9 Hz), 6.85(1H, s), 6.93(1H, d, J = 8.4 Hz), 7.42(1H, dd, J = 8.9 Hz, 2.0 Hz), 7.50(1H, d, J = 8.9 Hz), 7.53(1H, s), 7.69(1H, d, J = 1.8 Hz), 8.19(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.26(1H, brs), 8.31(1H, d, J = 2.6 Hz). 1132 3,4-Cl₂Ph— —F —F —H mp 204.5-204.5 1133 4-CF₃Ph— —F —F —H mp 230.0-231.5 1134 4-ClPh— —CH₃ —H —H ¹H NMR (CDCl₃) 2.08(3H, s), 2.42(4H, brs), 2.97(3H, s), 3.43(2H, s), 3.49(2H, brs), 3.60(2H, brs), 4.05(2H, s), 5.94 (2H, s), 6.48-6.52(2H, m), 6.74-6.89(5H, m), 7.41(2H, d, J = 8.6 Hz), 7.80(2H, d, J = 8.4 Hz), 8.08(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.21(1H, d, J = 2.6 Hz), 8.29(1H, s). 1135

—CH₃ —H —H ¹H NMR (CDCl₃) 2.11(3H, s), 2.43- 2.44(4H, m), 3.00(3H, s), 3.43(2H, s), 3.47- 3.49(2H, m), 3.63(2H, brs), 4.07(2H, s), 5.95(2H, s), 6.51-6.57(2H, m), 6.69- 6.93(6H, m), 7.19(1H, dd, J = 8.7 Hz, 7.5 Hz), 7.35-7.33(2H, m), 7.55(1H, brs), 7.86(1H, d, J = 15.8 Hz), 8.17-8.20(2H, m). 1136

—CH₃ —H —H ¹H NMR (CDCl₃) 2.10(3H, s), 2.43(4H, brs), 3.00(3H, s), 3.43(2H, s), 3.50(2H, brs), 3.64(2H, brs), 4.07(2H, s), 5.95 (2H, s), 6.50-6.56(2H, m), 6.67-6.92(6H, m), 7.07-7.19(2H, m), 7.31-7.36(1H, m), 7.47- 7.52(1H, m), 7.73(1H, brs), 7.80 (1H, d, J = 15.7 Hz), 8.14-8.20(2H, m). 1137

—CH₃ —H —H ¹H NMR (CDCl₃) 2.11(3H, s), 2.41- 2.44(4H, m), 3.00(3H, s), 3.43(2H, s), 3.47- 3.49(2H, m), 3.63(2H, brs), 4.06(2H, s), 5.94(2H, s), 6.09(1H, d, J = 14.7 Hz), 6.51- 6.56(2H, m), 6.70-6.96(7H, m), 7.30- 7.55(7H, m), 8.14(1H, d, J = 2.5 Hz), 8.14(1H, brs). 1138 4-CF₃Ph— —F —H —F mp 169.0-170.0 1139 3,4-Cl₂Ph— —F —H —F mp 138.0-139.0

TABLE 249

Example No. R₇₈₄ R₇₈₅ R₇₈₆ ¹H NMR (solvent) δppm 1140 3,4-Cl₂Ph— —CH₃ —CH₃ (DMSO-d₆) 2.00(3H, s), 2.93(3H, s), 3.23(1H, brs), 3.36(1H, brs), 3.63(1H, brs), 3.72(1H, brs), 4.07(1H, s), 4.27(1H, s), 4.29(2H, s), 4.47(2H, s), 5.99(2H, s), 6.43-6.63(2H, m), 6.77(1H, dd, J = 8.0 Hz, 1.5 Hz), 6.77-6.88(2H, m), 6.82(1H, d, J = 8.8 Hz), 6.90(1H, d, J = 8.6 Hz), 7.83(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.12(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.21(1H, d, J = 2.0 Hz), 8.40(1H, d, J = 2.6 Hz), 10.18(1H, s). 1141 4-CF₃Ph— —CH₃ —CH₃ (CDCl₃) 2.10(3H, s), 2.90-3.06(3H, m), 3.20- 3.34(2H, m), 3.62-3.84(2H, m), 4.08(2H, s), 4.20- 4.33(2H, m), 4.52(2H, s), 5.95(2H, s), 6.53(1H, dd, J = 8.6 Hz. 3.0 Hz), 6.58(1H, d, J = 3.0 Hz), 6.67- 6.79(3H, m), 6.82(1H, d, J = 8.9 Hz), 6.91(1H, d, J = 8.1 Hz), 7.74(2H, d, J = 8.2 Hz), 7.99(2H, d, J = 8.2 Hz), 8.10(1H, s), 8.15(1H, dd, J = 9.2 Hz, 2.3 Hz), 8.22(1H, d, J = 2.3 Hz). 1142 3,4-Cl₂Ph— —OCH₃ —C₂H₅ (CDCl₃) 1.17(3H, t, J = 6.4 Hz), 3.17-3.30(2H, m), 3.32-3.52(2H, m), 3.70(3H, s), 3.62-3.86(2H, m), 4.03(2H, s), 4.29(2H, s), 4.50 (2H, s), 5.95(2H, s), 6.22(1H, d, J = 8.9 Hz), 6.37(1H, s), 6.70(1H, d, J = 8.2 Hz), 6.75(1H, s), 6.76(1H, d, J = 8.9 Hz), 6.86(1H, d, J = 8.9 Hz), 6.94(1H, d, J = 8.7 Hz), 7.54(1H, d, J = 8.4 Hz), 7.70 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.98(1H, d, J = 2.0 Hz), 8.08(1H, s), 8.08(1H, dd, J = 8.9 Hz, 2.3 Hz), 8.20(1H, d, J = 2.3 Hz). 1143 4-CF₃Ph— —OCH₃ —C₂H₅ (CDCl₃) 1.18(3H, t, J = 6.7 Hz), 3.16-3.33(2H, m), 3.33-3.50(2H, m), 3.72(2H, s), 3.62-3.85(3H, m), 4.04(2H, s), 4.29(2H, s), 4.50 (2H, s), 5.95(2H, s), 6.23(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.38(1H, s), 6.71(1H, d, J = 8.1 Hz), 6.76(1H, s), 6.76(1H, d, J = 8.7 Hz), 6.88 (1H, d, J = 8.7 Hz), 6.95(1H, d, J = 8.7 Hz), 7.74(2H, d, J = 8.0 Hz), 7.99(2H, d, J = 8.0 Hz), 8.03(1H, s), 8.13(1H, dd, J = 8.7 Hz, 2.4 Hz), 8.21(1H, d, J = 2.4 Hz).

TABLE 250

Example No. R₇₈₇ R₇₈₈ Xb₁₆ Xb₁₇ Form ¹H NMR (solvent) δppm 1144 4-CF₃Ph— —H —N(CH₃)— —CH(CH₃)— free (CDCl₃) 1.30(3H, d, J = 6.3 Hz), 2.16-2.48 (4H, m), 2.77(3H, s), 3.26-3.56(3H, m), 3.39 (2H, s), 3.78(1H, brs), 4.56(1H, q, J = 6.6 Hz), 5.92(2H, s), 6.68-6.77(4H, m), 6.82(1H, s), 6.91(1H, d, J = 8.9 Hz), 7.04(2H, d, J = 9.1 Hz), 7.76(2H, d, J = 8.2 Hz), 7.90(1H, brs), 7.99(2H, d, J = 8.1 Hz), 8.17(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.25(1H, d, J = 2.6 Hz). 1145 4-CF₃Ph— —CH₃ —N(CH₃)— —CH(CH₃)— free (CDCl₃) 1.29(3H, d, J = 6.6 Hz), 2.14(3H, s), 2.14-2.22(1H, m), 2.29-2.35(2H, m), 2.48(1H, brs), 2.76(3H, s), 3.26-3.56(3H, m), 3.39(2H, s), 3.78(1H, brs), 4.57(1H, q, J = 6.6 Hz), 5.93 (2H, s), 6.58-6.62(2H, m), 6.63-6.75 (2H, m), 6.83(1H, brs), 6.86 (1H, d, J = 8.9 Hz), 6.95 (1H, d, J = 9.2 Hz), 7.76(2H, d, J = 8.3 Hz), 7.90(1H, brs), 7.99(2H, d, J = 8.3 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.23(1H, d, J = 2.5 Hz). 1146 3,4-Cl₂Ph— —H —CH₂— —NH— hydrochloride (DMSO-d₆) 2.78-3.10(2H, m), 3.10-3.35(4H, m), 4.00-4.19(2H, m), 4.18-4.32(4H, m), 6.07 (2H, s), 6.95-7.10(3H, m), 7.06(2H, d, J = 8.6 Hz), 7.23(1H, s), 7.30(2H, d, J = 8.6 Hz), 7.39 (1H, t, J = 5.5 Hz), 7.84(1H, d, J = 8.4 Hz), 7.97(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.19(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.25(1H, d, J = 2.0 Hz), 8.48(1H, d, J = 2.6 Hz), 10.62(1H, s). 1147 4-CF₃Ph— —H —CH₂— —NH— hydrochloride (DMSO-d₆) 2.80-3.05(2H, m), 3.11-3.38(4H, m), 4.00-4.35(4H, m), 4.24(2H, s), 6.07(2H, s), 6.98(1H, d, J = 8.7 Hz), 6.92- 7.10(2H, m), 7.06(2H, d, J = 8.6 Hz), 7.24(1H, d, J = 1.3 Hz), 7.30(2H, d, J = 8.6 Hz), 7.35- 7.45(1H, m), 7.93(2H, d, J = 8.3 Hz), 8.19(2H, d, J = 8.3 Hz), 8.22(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.51 (1H, d, J = 2.5 Hz), 10.70(1H, s).

TABLE 251

Example No. R₇₈₉ R₇₉₀ R₇₉₁ ¹H NMR (solvent) δppm 1148 4-CF₃Ph— —CH₃ —H (CDCl₃) 2.17(3H, s), 2.50-2.55(4H, m), 3.46(2H, s), 3.71-3.74 (2H, m), 4.26(2H, brs), 5.95(2H, s), 6.74- 6.75(2H, m), 6.86(1H, brs), 6.91-6.95(1H, m), 7.04(1H, d, J = 8.7 Hz), 7.43(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.56(1H, d, J = 2.3 Hz), 7.76(2H, d, J = 8.4 Hz), 7.94(1H, brs), 7.99(2H, d, J = 8.1 Hz), 8.20-8.23(2H, m), 9.17 (1H, brs). 1149 3,4-Cl₂Ph— —CH₃ —H (CDCl₃) 2.18(3H, s), 2.50-2.56(4H, m), 3.47(2H, s), 3.72-3.75 (2H, m), 4.25-4.29(2H, m), 5.96(2H, s), 6.75(2H, brs), 6.86(1H, brs), 6.93(1H, d, J = 8.7 Hz), 7.04(1H, d, J = 8.7 Hz), 7.44(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.56-7.57(1H, m), 7.58(1H, d, J = 8.3 Hz), 7.70 (1H, brs), 7.71(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.98(1H, d, J = 2.1 Hz), 8.15-8.21(2H, m), 9.16(1H, brs). 1150 3,4-Cl₂Ph— —CH₃ —CH₃ (DMSO-d₆) 2.10-2.49(7H, m), 3.26-3.57(9H, m), 5.96- 5.99(2H, m), 6.69-6.89(3H, m), 7.05-7.11(2H, m), 7.16-7.28(1H, m), 7.30-7.37(1H, m), 7.84(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.18- 8.22(2H, m), 8.42-8.47(1H, m), 10.54(1H, brs). 1151 4-CF₃Ph— —CH₃ —CH₃ (DMSO-d₆) 2.10-2.46(7H, m), 3.26-3.57(9H, m), 5.96- 6.00(2H, m), 6.69-6.89(3H, m), 7.06-7.12(2H, m, 7.17-7.29(1H, m), 7.31-7.37(1H, m), 7.94(1H, d, J = 8.6 Hz), 8.16(2H, d, J = 8.6 Hz), 8.21-8.25(2H, m), 8.45-8.49(1H, m), 10.61(1H, brs). 1152 4-CF₃Ph— —H —SO₂CH₃ (CDCl₃) 2.45(4H, brs), 3.19(3H, s), 3.39(2H, brs), 3.46(2H, s), 3.62(2H, brs), 4.52(2H, s), 5.94(2H, s), 6.74(2H, brs), 6.84(1H, brs), 7.00(1H, d, J = 8.7 Hz), 7.10(2H, d, J = 8.7 Hz), 7.57(2H, d, J = 8.7 Hz), 7.75(2H, d, J = 8.1 Hz), 8.00(2H, d, J = 8.1 Hz), 8.15- 8.24(2H, m), 8.31(1H, brs). 1153 3,4-Cl₂Ph— —CH₃ —SO₂CH₃ (CDCl₃) 2.16(3H, s), 2.46(4H, brs), 3.20(3H, s), 3.40(2H, brs), 3.47(2H, s), 3.63(2H, brs), 4.52(2H, s), 5.94(2H, s), 6.70-6.77 (2H, m), 6.83(1H, brs), 6.95(1H, d, J = 9.1 Hz), 6.99(1H, d, J = 8.7 Hz), 7.38- 7.57(3H, m), 7.71(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.97(1H, d, J = 2.0 Hz), 8.11(1H, brs), 8.17(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.6 Hz). 1154 4-CF₃Ph— —CH₃ —SO₂CH₃ (CDCl₃) 2.18(3H, s), 2.42-2.46(4H, m), 3.21(3H, s), 3.39-3.40 (2H, m), 3.44(2H, s), 3.62(2H, brs), 4.53(2H, s), 5.94(2H, s), 6.70-6.77(2H, m), 6.84(1H, brs), 6.96-7.03(2H, m), 7.41-7.46 (2H, m), 7.76(2H, d, J = 8.2 Hz), 7.98-8.01(3H, m), 8.21(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.26(1H, d, J = 2.3 Hz). 1155 3,4-Cl₂Ph— —H —SO₂CH₃ (CDCl₃) 2.41-2.45(4H, m), 3.19(3H, s), 3.38(2H, brs), 3.44(2H, s), 3.61(2H, brs), 4.52(2H, s), 5.94(2H, s), 6.72-6.74(2H, m), 6.83(1H, brs), 6.98(1H, d, J = 8.7 Hz), 7.09(2H, d, J = 8.7 Hz), 7.55(1H, d, J = 8.4 Hz), 7.56(2H, d, J = 8.7 Hz), 7.72(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.98(1H, d, J = 2.1 Hz), 8.18(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.27(1H, brs), 8.30(1H, d, J = 2.1 Hz).

TABLE 252

Example No. R₇₉₂ R₇₉₃ R₇₉₄ ¹H NMR (CDCl₃) δppm 1156 4-CF₃Ph— —H —CH₃ 1.21(3H, t, J = 6.8 Hz), 2.05-2.14(1H, m), 2.44- 2.51(1H, m), 2.70-2.74(1H, m), 2.83-3.32(6H, m), 3.55-3.59(1H, m), 3.84-4.08(4H, m), 5.94(2H, s), 6.66(2H, d, J = 8.9 Hz), 6.74(2H, brs), 6.81-6.85 (2H, m), 6.97(2H, d, J = 8.4 Hz), 7.72(2H, d, J = 8.3 Hz), 7.98(2H, d, J = 8.3 Hz), 8.11(1H, d, J = 9.1 Hz), 8.25(1H, d, J = 2.5 Hz), 8.31(1H, brs). 1157 4-CF₃Ph— —CH₃ —H 1.26-1.39(3H, m), 1.99-2.04(1H, m), 2.13- 2.17(1H, m), 2.64-2.67(1H, m), 2.79-2.83(1H, m), 2.98(4H, brs), 3.31-3.53(3H, m), 3,97- 4.66(3H, m), 5.95(2H, s), 6.64(2H, d, J = 9.1. Hz), 6.74(2H, brs), 6.82(1H, d, J = 8.9 Hz), 6.87(1H, brs), 6.96(2H, d, J = 9.1 Hz), 7.71(2H, d, J = 7.9 Hz), 7.98(2H, d, J = 8.3 Hz), 8.10(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.25(1H, d, J = 2.5 Hz), 8.40(1H, brs). 1158 3,4-Cl₂Ph— —H —CH₃ 1.21(3H, t, J = 6.8 Hz), 2.07-2.14(1H, m), 2.43- 2.52(1H, m), 2.70(1H, brs), 2.83-3.32(6H, m), 3.55-3.60(1H, m), 3.83-4.08(4H, m), 5.94(2H, s), 6.64(2H, d, J = 9.1 Hz), 6.74(2H, brs), 6.81(1H, d, J = 8.9 Hz), 6.85(1H, brs), 6.96(2H, d, J = 8.7 Hz), 7.53(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.98(1H, d, J = 2.0 Hz), 8.05(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.5 Hz), 8.31(1H, brs). 1159 3,4-Cl₂Ph— —CH₃ —H 1.26-1.39(3H, m), 1.99-2.17(2H, m), 2.64- 2.68(1H, m), 2.79-2.84 (1H, m), 2.99(4H, brs), 3.31-3.54(3H, m), 4.01-4.68(3H, m), 5.95(2H, s), 6.64(2H, d, 4 = 9.1 Hz), 6.74(2H, brs), 6.81(1H, d, J = 8.9 Hz), 6.87(1H, brs), 6.96(2H, d, J = 8.9 Hz), 7.53(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.98(1H, d, J = 2.0 Hz), 8.06(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.24(1H, d, J = 2.3 Hz), 8.26(1H, brs).

TABLE 253

Example No. R₇₉₅ R₇₉₆ R₇₉₇ ¹H NMR (CDCl₃) δppm 1160 3,4-Cl₂Ph— —H —CH₃ 1.16-1.19(6H, m), 2.04-2.14(1H, m), 2.43-2.52(1H, m), 2.66-2.74(1H, m), 2.83-3.36(5H, m), 3.59- 3.63(1H, m), 3.84-4.08(4H, m), 5.94(2H, s), 6.59(2H, d, J = 8.9 Hz), 6.74(2H, brs), 6.79(1H, d, J = 8.9 Hz), 6.85(1H, brs), 6.92(2H, d, J = 8.9 Hz), 7.50(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.98(1H, d, J = 2.0 Hz), 8.03(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.3 Hz), 8.64(1H, brs). 1161 4-CF₃Ph— —H —CH₃ 1.09-1.15(6H, m), 2.04-2.13(1H, m), 2.43-2.51(1H, m), 2.66-2.74(1H, m), 2.83-3.38(5H, m), 3.58- 3.63(1H, m), 3.84-4.08(4H, m), 5.94(2H, s), 6.61(2H, d, J = 8.9 Hz), 6.74(2H, brs), 6.81(1H, d, J = 8.9 Hz), 6.85(1H, brs), 6.94(2H, d, J = 8.3 Hz), 7.71(2H, d, J = 7.8 Hz), 7.99(2H, d, J = 8.1 Hz), 8.10(1H, d, J = 9.1 Hz), 8.26(1H, d, J = 2.5 Hz), 8.50(1H, brs). 1162 3,4-Cl₂Ph— —CH₃ —H 1.15(3H, t, J = 7.1 Hz), 1.26-1.43(3H, m), 2.00(1H, brs), 2.13(1H, brs), 2.64-2.68(1H, m), 2.79- 2.83(1H, m), 3.02-4.68(9H, m), 5.95(2H, s), 6.61(2H, d, J = 9.1 Hz), 6.74(2H, brs), 6.81(1H, d, J = 8.7 Hz), 6.87(1H, brs), 6.94(2H, d, J = 8.9 Hz), 7.53(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.99(1H, d, J = 2.0 Hz), 8.06(1H, d, J = 8.9 Hz), 8.25(1H, d, J = 2.6 Hz), 8.32(1H, brs). 1163 4-CF₃Ph— —CH₃ —H 1.15(3H, t, J = 6.9 Hz), 1.26-1.39(3H, m), 1.99(1H, brs), 2.13(1H, brs), 2.63-2.67(1H, m), 2.79- 2.83(1H, m), 3.00-4.67(9H, m), 5.95(2H, s), 6.61(2H, d, J = 8.4 Hz), 6.74(2H, brs), 6.82(1H, d, J = 8.7 Hz), 6.87(1H, brs), 6.95(2H, d, J = 8.9 Hz), 7.71(2H, d, J = 7.9 Hz), 7.99(2H, d, J = 8.1 Hz), 8.10(1H, d, J = 8.3 Hz), 8.27(1H, d, J = 2.5 Hz), 8.38(1H, brs).

TABLE 254

Example No. R₇₉₈ R₇₉₉ ¹H NMR (CDCl₃) δppm 1164 4-CF₃Ph— —H 2.52(4H, brs), 2.64(4H, brs), 3.12(2H, s), 3.45(2H, brs), 5.94(2H, s), 6.75 (2H, brs), 6.86(1H, brs), 6.95(1H, d, J = 8.7 Hz), 7.11(2H, d, J = 8.9 Hz), 7.60(2H, d, J = 8.9 Hz), 7.76(2H, d, J = 8.3 Hz), 7.98(1H, brs), 8.00(2H, d, J = 8.3 Hz), 8.21(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.26(1H, d, J = 2.5 Hz), 9.16(1H, brs). 1165 3,4-Cl₂Ph— —H 2.52(4H, brs), 2.62-2.64(4H, m), 3.12(2H, s), 3.45(2H, brs), 5.95(2H, s), 6.75(2H, brs), 6.86(1H, brs), 6.94(1H, d, J = 8.7 Hz), 7.10(2H, d, J = 8.9 Hz), 7.57(1H, d, J = 8.4 Hz), 7.59(2H, d, J = 8.9 Hz), 7.72(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.99(2H, brs), 8.17(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.25(1H, d, J = 2.8 Hz), 9.17(1H, brs). 1166 3,4-Cl₂Ph— —CH₃ 2.44(8H, brs), 2.95(2H, s), 3.26(3H, s), 3.39(2H, s), 5.92(2H, s), 6.71(2H, brs), 6.81(1H, brs), 7.02(1H, d, J = 8.7 Hz), 7.14-7.22(4H, m), 7.58(1H, d, J = 8.4 Hz), 7.77(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.05(1H, d, J = 2.1 Hz), 8.27(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.32(1H, d, J = 2.0 Hz), 8.33(1H, brs). 1167 4-CF₃Ph— —CH₃ 2.50(8H, brs), 2.95(2H, s), 3.24(3H, s), 3.47(2H, s), 5.92(2H, s), 6.72(2H, brs), 6,81(1H, brs), 7.02(1H, d, J = 8.7 Hz), 7.13-7.21(4H, m), 7.74(2H, d, J = 8.4 Hz), 8.05(2H, d, J = 8.1 Hz), 8.30(1H, dd, 3 = 8.9 Hz, 2.5 Hz), 8.35(1H, d, J = 2.3 Hz), 8.61(1H, brs).

TABLE 255

Example No. R₈₀₀ R₈₀₁ M Form ¹H NMR (solvent) δppm 1168 3,4-Cl₂Ph— piperonyl 2 hydrochloride (DMSO-d₆) 2.60-2.61(2H, m), 2.75- 3.08(6H, m), 3.22-3.60(5H, m), 4.03(1H, d, J = 13.9 Hz), 4.20(2H, d, J = 4.3 Hz), 4.46(1H, d, J = 13.9 Hz), 6.06(2H, s), 6.73(2H, d, J = 8.9 Hz), 6.93-6.99(5H, m), 7.20(1H, brs), 7.83(1H, d, J = 8.4 Hz), 7.96(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.14(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.23(1H, d, J = 2.0 Hz), 8.45(1H, d, J = 2.6 Hz), 10.57(1H, brs), 11.00(1H, brs). 1169 4-CF₃Ph— piperonyl 2 hydrochloride (DMSO-d₆) 2.60-2.62(2H, m), 2.88- 3.08(6H, m), 3.23-3.60(5H, m), 4.01-4.06(1H, m), 4.20-4.21(2H, m), 4.43-4.49(1H, m), 6.07(2H, s), 6.73(2H, d, J = 8.6 Hz), 6.94- 6.99(5H, m), 7.20(1H, brs), 7.93(2H, d, J = 8.2 Hz), 8.14- 8.19(3H, m), 8.47(1H, d, J = 2.5 Hz), 10.64(1H, brs), 11.00(1H, brs). 1170 4-CF₃Ph— benzyl 0 free (CDCl₃) 2.25(4H, t, J = 4.9 Hz), 3.19(3H, s), 3.23(4H, t, J = 4.9 Hz), 3.43(2H, s), 6.95(1H, d, J = 8.7 Hz), 7.08(4H, s), 7.20-7.32(5H, m), 7.75(2H, d, J = 8.0 Hz), 8.02(2H, d, J = 8.0 Hz), 8.24(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.31(1H, d, J = 2.5 Hz), 8.34(1H, s). 1171 3,4-Cl₂Ph— benzyl 0 hydrochloride (DMSO-d₆) 2.70-3.00(2H, m), 3.14(3H, s), 2.95-3.30(4H, m), 3.72(2H, d, J = 13.7 Hz), 4.29(2H, s), 7.08(1H, d, J = 8.7 Hz), 7.11(2H, d, J = 8.9 Hz), 7.23(2H, d, J = 8.9 Hz), 7.39-7.48(3H, m), 7,51- 7.60(2H, m), 7.84(1H, d, J = 8.5 Hz), 7.97(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.22(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.25(1H, d, J = 2.0 Hz), 8.53(1H, d, J = 2.6 Hz), 10.67(1H, s).

TABLE 256

Example No. R₈₀₂ R₈₀₃ R₈₀₄ ¹H NMR (CDCl₃) δppm 1172 3,4-Cl₂Ph— —H —CH₃ 2.34(3H, s), 2.34-2.50(4H, m), 2.78(3H, s), 3.42(2H, s), 3.50-3.70(4H, m), 3.80(2H, s), 5.95(2H, s), 6.70-6.80(2H, m), 6.85-6.89(2H, m), 7.26-7.35(1H, m), 7.40(1H, d, J = 2.8 Hz), 7.51 (1H, d, J = 8.9 Hz), 7,57-7.61(2H, m), 7.74(1H, dd, J = 8.3 Hz, 2.0 Hz), 8.01(1H, d, J = 2.0 Hz), 8.29(1H, s). 1173 4-CF₃Ph— —H —CH₃ 2.36(3H, s), 2.36-2.50(4H, m), 2.79(3H, s), 3.42(2H, s), 3.50-3.65(4H, m), 3.80(2H, s), 5.94(2H, s), 6.70-6.75(2H, m), 6.85-6.90(2H, m), 7.30(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.40(1H, d, J = 2.8 Hz), 7.51(1H, d, J = 8.8 Hz), 7.68(1H, brs), 7.76-7.80(2H, m), 8.01-8.04(2H, m), 8.34(1H, s). 1174 3,4-Cl₂Ph— —CH₃ —H 2.30-2.44(4H, m), 2.44(3H, s), 2.79(3H, s), 3.42(2H, s), 3.50-3.65(4H, m), 3.80(2H, s), 5.95(2H, s), 6.65-6.81(3H, m), 6.85(1H, s), 7.29(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.41(1H, d, J = 2.7 Hz), 7.49(1H, d, J = 8.8 Hz), 7.59(1H, d, J = 8.3 Hz), 7.67(1H, brs), 7.72(1H, dd, J = 8.3 Hz, 2.1 Hz), 8.00(1H, d, J = 2.0 Hz), 8.09(1H, d, J = 8.7 Hz). 1175 4-CF₃Ph— —CH₃ —H 2.35-2.45(4H, m), 2.45(3H, s), 2.79(3H, s), 3.42(2H, s), 3.50-3.65(4H, m), 3.80(2H, s), 5.95(2H, s), 6.65-6.82(2H, m), 6.85(1H, s), 7.30(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.41(1H, d, J = 2.8 Hz), 7.50(1H, d, J = 8.8 Hz), 7.72(1H, brs), 7.77-7.80(2H, m), 8.00-8.03(2H, m), 8.15(1H, d, J = 8.6 Hz).

TABLE 257

Example No. R₈₀₅ R₈₀₆ R₈₀₇ R₈₀₈ Form ¹H NMR (DMSO-d₆) δppm 1176 3,4-Cl₂Ph— —H —H

free 3.14(1H, dd, J = 14.0 Hz, 9.4 Hz), 3.40(1H, dd, J = 14.0 Hz, 4.5 Hz), 4.93(1H, dd, J = 9.4 Hz, 4.5 Hz), 7.07(1H, d, J = 8.9 Hz), 7.07(2H, d, J = 8.4 Hz), 7.29(2H, d, J = 8.4 Hz), 7.84(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.20(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.22(1H, d, J = 2.0 Hz), 8.48(1H, d, J = 2.5 Hz), 10.56(1H, s), 12.06(1H, s). 1177 4-CF₃OPh— —CH₃ —H

hydro- chloride 2.09(3H, s), 3.09(1H, dd, J = 14.3 Hz, 9.6 Hz), 3.40(1H, dd, J = 14.3 Hz, 4.3 Hz), 4.93(1H, dd, J = 9.6 Hz, 4.3 Hz), 6.99(1H, d, J = 8.1 Hz), 7.02(1H, d, J = 8.9 Hz), 7.12(1H, d, J = 8.1 Hz), 7.20 (1H, s), 7.55(2H, d, J = 8.8 Hz), 8.10(2H, d, J = 8.8 Hz), 8.20(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.44(1H, d, J = 2.6 Hz), 10.54(1H, s), 12.10(1H, s). 1178 3,4-Cl₂Ph— —H —CH₃ morpholino hydro- 1.70(3H, d, J = 6.9 Hz), 2.94-3.01 chloride (2H, m), 3.63-4.02(6H, m), 4.50 (1H, t, J = 6.6 Hz), 7.13(1H, d, J = 9.1 Hz), 7.23(2H, d, J = 8.7 Hz), 7.64 (2H, d, J = 8.7 Hz), 7.85(1H, d, J = 8.4 Hz), 7.96(1H, dd, J = 8.4 Hz, 2.2 Hz), 8.23(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.1 Hz), 8.54(1H, d, J = 2.1 Hz), 10.63(1H, brs), 10.89(1H, brs). 1179 4-CF₃Ph— —H —CH₃ morpholino hydro- 1.72(3H, d, J = 6.6 Hz), 2.92(2H, chloride brs), 3.35(2H, brs), 3.69-3.99(4H, m), 4.49(1H, brs), 7.14(1H, d, J = 8.7 Hz), 7.22(2H, d, J = 8.3 Hz), 7.69(2H , d, J = 8.3 Hz), 7.94(2H, d, J = 8.3 Hz), 8.20(2H, d, J = 8.1 Hz), 8.28(1H, d, J = 8.9 Hz), 8.58(1H, brs), 10.77(1H, brs), 11.47(1H, brs). 1180 Ph— —H —CH₃ morpholino hydro- 1.70(3H, d, J = 6.8 Hz), 2.94(2H, chloride brs), 3.38-3.43(2H, m), 3.62- 4.02(4H, m), 4.50(1H, t, J = 6.6 Hz), 7.12(1H, d, J = 8.7 Hz), 7.22(2H, d, J = 8.6 Hz), 7.52- 7.65(5H, m), 7.96-8.00(2H, m), 8.26(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.56(1H, d, J = 2.8 Hz), 10.47(1H, brs), 10.91(1H, brs).

TABLE 258 Example No. Chemical stracture mp (° C.) 1181

203.0-204.0 1182

186.0-187.0 1183

165.0-166.0 1184

122.0-124.0 1185

155.0-157.0 1186

182.0-183.5 1187

117.0-118.0 1188

160.0-161.0

TABLE 259

Example No. R₈₀₉ R₈₁₀ R₈₁₁ Xb₁₈ ¹H NMR (CDCl₃) δppm 1189 4-CF₃Ph— —COOCH₃ benzyl —O— 2.62(4H, brs), 3.23(4H, brs), 3.58(2H, s), 3.67(3H, s), 6.95(1H, d, J = 9.7 Hz), 7.06-7.14(2H, m), 7.26-7.36(5H, m), 7.49 (1.11, d, J = 2.3 Hz), 7.74(2H, d, J = 8.3 Hz), 7.87(1H, s), 7.98(2H, d, J = 8.1 Hz), 8.16-8.18(2H, m). 1190 3,4-Cl₂Ph— —H —COOC(CH₃)₃ —O— 1.49(9H, s), 3.11(4H, t, J = 4.8 Hz), 3.58(4H, t, J = 4.8 Hz), 6.92(1H, d, J = 9.0 Hz), 6.96(2H, d, J = 8.5 Hz), 7.06(2H, d, J = 8.5 Hz), 7.58(1H, d, J = 8.5 Hz), 7.70 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.74(1H, brs), 7.98(1H, d, J = 2.0 Hz), 8.15(1H, brd, J = 9.0 Hz), 8.24(1H, d, J = 2.5 Hz). 1191 4-CF₃Ph— —H —COOC(CH₃)₃ —O— 1.49(9H, s), 3.11(4H, t, J = 5.0 Hz), 3.58(4H, t, J = 5.0 Hz), 6.93(1H, d, J = 9.0 Hz), 6.96(2H, d, J = 9.0 Hz), 7.06(2H, d, J = 9.0 (2H, brs), 7.99(2H, d, J = 8.0 Hz), 8.19(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.25(1H, d, J = 2.5 Hz). 1192 4-CF₃Ph— —H —CH₂COOC₂H₅ —N(CH₃)— 1.30(3H, t, J = 7.1 Hz), 2.77(4H, t, J = 5.0 Hz), 3.28(4H, t, J = 5.0 Hz), 3.29(2H, s), 3.42(3H, s), 4.22(2H, q, J = 7.1 Hz), 6.47(1H, d, J = 9.2 Hz), 6.96(2H, d, J = 9.0 Hz), 7.15(2H, d, J = 9.0 Hz), 7.69(1H, brs), 7.70 (1H, d, J = 2.5 Hz), 7.74(2H, d, J = 8.1 Hz), 7.98(2H, d, J = 8.1 Hz), 8.26 (1H, d, J = 2.5 Hz).

TABLE 260

Example No. R₈₁₂ R₈₁₃ Xb₁₉ Xb₂₀ ¹H NMR (solvent) δppm 1193 3,4-Cl₂Ph— —COOC(CH₃)₃ —CO— —CH₂— (CDCl₃) 1.51(9H, s), 3.75(2H, m), 3.79(2H, m), 4.26(2H, s), 6.98(1H, d, J = 8.8 Hz), 7.14(2H, dd, J = 6.9 Hz, 2.1 Hz), 7.28(2H, dd, J = 6.9 Hz, 2.1 Hz), 7.58(1H, d, J = 8.3 Hz), 7.72(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.99(1H, d, J = 2.1 Hz), 8.13(1H, dd, J = 8.8 Hz, 2.7 Hz), 8.29(1H, d, J = 2.7 Hz). 1194 3,4-Cl₂Ph— piperonyl —CH₂— —CO— (DMSO-d₆) 3.22-3,50(4H, m), 3.84(2H, s), 4.50(2H, s), 6.00(2H, s), 6.77(1H, dd, J = 8.0 Hz, 1.4 Hz), 6.84(1H, d, J = 1.4 Hz), 6.87(1H, d, J = 8.0 Hz), 6.98(2H, d, J = 8.6 Hz), 6.97-7.06(3H, m), 7.84(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, d, J = 2.0 Hz), 8.44(1H, d, J = 2.3 Hz), 10.51(1H, s). 1195 4-CF₃Ph— piperonyl —CH₂— —CO— (DMSO-d₆) 3.27-3.40(2H, m), 3.40- 3.50(2H, m), 3.85(2H, s), 4.50(2H, s), 6.00(2H, s), 6.77(1H, dd, J = 7.9 Hz, 1.5 Hz), 6.84(1H, d, J = 1.5 Hz), 6.88(1H, d, J = 7.9 Hz), 6.95-7.07(5H, m), 7.93(2H, d, J = 8.1 Hz), 8.16(2H, d, J = 8.1 Hz), 8.17(1H, dd, J = 8.8 Hz, 2.5 Hz), 8.46(1H, d, J = 2.5 Hz), 10.60(1H, s).

TABLE 261

Example No. R₈₁₄ R₈₁₅ Xb₂₁ ¹H NMR (CDCl₃) δppm 1196 3,4-Cl₂Ph— —COOC₂H₅ —O— 1.28(3H, t, J = 7.0 Hz), 1.88-1.93(2H, m), 2.03(2H, brd, J = 10.0 Hz), 2.42(1H, m), 2.78(1H, t, J = 10.5 Hz), 3.59(2H, dt, J = 12.5 Hz, 3.5 Hz), 4.16(2H, q, J = 7.0 Hz), 6.90(1H, d, J = 9.0 Hz), 6.95(2H, d, J = 9.0 Hz), 7.03(2H, d, J = 9.0 Hz), 7.58(1H, d, J = 8.5 Hz), 7.70(1H, brs), 7.71(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.98(1H, d, J = 2.0 Hz), 8.14(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.24(1H, d, J = 2.5 Hz). 1197 3,4-Cl₂Ph— —CH₂COOC₂H₅ —O— 1.27(3H, t, J = 7.0 Hz), 1.40-1.46(2H, m), 1.82(2H, brd, J = 13.0 Hz), 1.90(1H, m), 2.27(2H, d, J = 7.0 Hz), 2.69(2H, brt, J = 13.0 Hz), 3.57(2H, brd, J = 12.0 Hz), 4.15 (2H, q, J = 7,0 Hz), 6.83(1H, d, J = 9.0 Hz), 6.90(2H, d, J = 9.0 Hz), 6.97(2H, d, J = 9.0 Hz), 7.49(1H, d, J = 8.5 Hz), 7.68(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.95(1H, d, J = 2.0 Hz), 8.10(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.21(1H, d, J = 2.5 Hz), 8.48(1H, brs). 1198 4-CF₃Ph— —CH₂COOC₂H₅ —O— 1.28(3H, t, J = 7.1 Hz), 1.46(2H, qd, J = 12.2 Hz, 3.4 Hz), 1.86(2H, d, J = 13.5 Hz), 1.85- 2.10(1H, m), 2.30(2H, d, J = 7.1 Hz), 2.76(2H, td, J = 12.2 Hz, 2.2 Hz), 3.42(3H, s), 3.68(2H, d, J = 12.2 Hz), 4.16(2H, q, J 7.1 Hz), 6.46(1H, d, J = 9.0 Hz), 6.96(2H, d, J = 8.9 Hz), 7.13(2H, d, J = 8.9 Hz), 7.72(1H, dd, J = 9.0 Hz, 2.5 Hz), 7.73(1H, d, J = 2.5 Hz), 7.74(2H, d, J = 8.2 Hz), 7.98(2H, d, J = 8.2 Hz), 8.26(1H, d, J = 2.5 Hz). 1199 4-CF₃Ph— —CH₂OOC₂H₅ —O— 1.28(3H, t, J = 7.0 Hz), 1.44(2H, dq, J = 3.5 Hz, 12.0 Hz), 1.84(2H, brd, J = 13.0 Hz), 1.93(1H, m), 2.29(2H, d, J = 7.0 Hz), 2.73(2H, dt, J = 2.5 Hz, 12.0 Hz), 3.61(2H, brd, J = 12.0 Hz), 4.15(2H, q, J = 7.0 Hz), 6.91(1H, d, J = 9.0 Hz), 6.96(2H, d, J = 9.0 Hz), 7.04(2H, d, J = 9.0 Hz), 7.74(1H, brs), 7.77(2H, d, J = 8.5 Hz), 7.99(2H, d, J = 8.5 Hz), 8.18(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.25(1H, d, J = 2.5 Hz). 1200 4-CF₃Ph— —COOC₂H₅ —O— 1.26(3H, t, J = 7.1 Hz),1.17-1.98(4H, m), 2.35-2.43(1H, m), 2.68-2.76(2H, m), 3.51- 3.55(2H, m), 4.14(2H, q, J = 7.1 Hz), 6.78(1H, d, J = 8.9 Hz), 6.85-6.95(4H, m), 7.61(2H, d, J = 8.2 Hz), 7.93(2H, d, J = 8.1 Hz), 8.09(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.6 Hz), 9.00(1H, s).

TABLE 262

Example No. R₈₁₆ R₈₁₇ R₈₁₈ ¹H NMR (CDCl₃) δppm 1201 4-CF₃Ph— —CH₃

1.31-1.43(2H, m), 1.80-1.98(3H, m), 2.10(3H, s), 2.26(2H, d, J = 6.8 Hz), 2.38-2.44(4H, m), 2.66(2H, t, J = 12.2 Hz), 3.46-3.63(8H, m), 6.72-6.81(3H, m), 6.90(1H, d, J = 8.6 Hz), 7.26- 7.33(5H, m), 7.70(2H, d, J = 8.2 Hz), 8.00(2H, d, J = 8.1 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.25(1H, d, J = 2.5 Hz), 8.60(1H, s). 1202 4- CF₃Ph— —CH₃

1.31-1.43(2H, m), 1.79-1.98(3H, m), 2.11(3H, s), 2.26(2H, d, J = 6.8 Hz), 2.36-2.39(4H, m), 2.66(2H, t, J = 12.0 Hz), 3.42(2H, s), 3.45-3.61(6H, m), 6.70-6.92(7H, m), 7.70(2H, d, J = 8.2 Hz), 7.99(2H, d, J = 8.1 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.25(1H, d, J = 2.5 Hz), 8.55(1H, s). 1203 3,4- Cl₂Ph— —CH₃

1.29-1.41(2H, m), 1.77-1.98(3H, m), 2.09(3H, s), 2.26(2H, d, J = 6.8 Hz), 2.34-2.40(4H, m), 2.62(2H, t, J = 12.0 Hz), 3.41(2H, s), 3.46-3.60(6H, m), 6.70-6.90(7H, m), 7.49(1H, d, J = 8.4 Hz), 7.73(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.99(1H, d, J = 2.0 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J =2.6 Hz), 8.99(1H, s). 1204 3,4- Cl₂Ph— —CH₃

1.29-1.41(2H, m), 1.77-1.98(3H, m), 2.09(3H, s), 2.26(2H, d, J = 6.8 Hz), 2.37-2.44(4H, m), 2.63(2H, t, J = 11.9 Hz), 3.48-3.63(8H, m), 6.70-6.78(2H, m), 6.88(1H, d, J = 8.6 Hz), 7.26- 7.33(6H, m), 7.48(1H, d, J = 8.4 Hz), 7.72(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.99(1H, d, J = 2.1 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.26(1H, d, J = 2.6 Hz), 9.03(1H, s). 1205 4- —OCH₃ —OC₂H₅ 1.27(3H, t, J = 7.1 Hz), 1.39-1.42(2H, CF₃Ph— m), 1.80-1.85(3H, m), 2.28(2H, d, J = 6.9 Hz), 2.70(3H, t, J = 10.1 Hz), 3.56(2H, d, J = 12.2 Hz), 3.66(3H, s), 4.14(2H, q, J = 7.3 Hz), 6.43(1H, dd, J = 8.7 Hz, 2.5 Hz), 6.51(1H, d, J = 2.5 Hz), 6.78(1H, d, J = 8.9 Hz), 6.90(1H, d, J = 8.7 Hz), 7.63(2H, d, J = 8.6 Hz), 7.96(2H, d, J = 8.2 Hz), 8.08(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.18(1H, d, J = 2.6 Hz), 8.95(1H, s).

TABLE 263

Example No. R₈₁₉ R₈₂₀ mp (° C.) or ¹H NMR (solvent) δppm 1206 3,4- morpholino ¹H NMR (DMSO-d₆) 3.07-3.10(4H, m), 3.73- Cl₂Ph— 3.77(4H, m), 6.96-7.04(5H, m), 7.83(1H, d, J = 8.2 Hz), 7.94(1H, dd, J = 8.2 Hz, 2.0 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, d, J = 2.0 Hz), 8.45(1H, d, J = 2.6 Hz), 10.51(1H, brs). 1207 3,4- Cl₂Ph—

¹H NMR (CDCl₃) 1.72-1.90(4H, m), 2.40- 2.53(2H, m), 3.20-3.32(2H, m), 458(2N, s), 6.95(1H, d, J = 8.9 Hz), 7.08(2H, d, J = 8.6 Hz), 7.27(2H, d, J = 8.6 Hz), 7.58(1H, d, J = 8.6 Hz), 7.73(1H, dd, J = 8.6 Hz, 2.0 Hz), 8.01(1H, d, J = 2.0 Hz), 8.11(1H, s), 8.19(1H, dd, J = 8.9 Hz, 2.3 Hz), 8.28(1H, d, J = 2.3 Hz). 1208 4-CF₃Ph— —NHCONHPh mp 240.0-240.5 1209 3,4- Cl₂Ph—

¹H NMR (CDCl₃) 1.28(3H, t, J = 7.0 Hz), 1.60- 1.70(2H, m), 1.83(1H, m), 2.03(1H, m), 2.69(1H, m), 2.82(1H, brt, J = 12.0 Hz), 3.03(1H, dd, J = 12.0 Hz, 10.0 Hz), 3.42(1H, brd, J = 12.0 Hz), 3.65(1H, brd, J = 12.0 Hz), 4.17(2H, q, J = 7.0 Hz), 6.90(1H, d, J = 9.0 Hz), 6.97(2H, d, J = 9.0 Hz), 7.03(2H, d, J = 9.0 Hz), 7.58(1H, d, J = 8.5 Hz), 7.70 (IH, dd, J = 8.5 Hz, 2.0 Hz), 7.75(1H, s), 7.97(1H, d, J = 2.0 Hz), 8.14(1H, brd, 3 = 9.0 Hz), 8.23(1H, d, J = 2.5 Hz). 1210 3,4- Cl₂Ph—

¹H NMR (DMSO-d₆) 2.33-2.38(4H, m), 2.65- 2.83(2H, m), 3.41(2H, s), 3.45-3.57(4H, m), 3.65-3 75(1H, m), 3.91-4.08(2H, m), 6.00(2H, s), 6.76(1H, dd, J = 1.5 Hz, 8.1 Hz), 6.84- 6.88(2H, m), 7.07(1H, d, J = 8.9 Hz), 7.14(2H, d, J = 8.9 Hz), 7.67(2H, d, J = 9.1 Hz), 7.85(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 2.0 Hz, 8.4 Hz), 8.19(1H, dd, J = 2.6 Hz, 8.9 Hz), 8.23(1H, d, J = 2.1 Hz), 8.47(1H, d, J = 2.6 Hz), 10.56(1H s). 1211 4-CF₃Ph—

¹H NMR (DMSO-d₆) 2.33-2.38(4H, m), 2.65- 2.83(2H, m), 3.41(2H, s), 3.51(4H, brs), 3.65- 3.75(1H, m), 3.91-4.08(2H, m), 5.99(2H, s), 6.76(1H, dd, J = 1.3 Hz, 7.9 Hz), 6.84-6.88(2H, m),), 7.08(1H, d, J = 8.9 Hz), 7.15(2H, d, J = 6.9 Hz), 7.68(2H, d, J = 6.9 Hz), 7.94(2H, d, J = 8 6 Hz), 8.17(2H, d, J = 8.1 Hz), 8.23(1H, dd, J = 2.6 Hz, 8.9 Hz), 8.50(1H, d, J = 2.6 Hz), 10.64(1H, s).

TABLE 264

Example No. R₈₂₁ ¹H NMR (DMSO-d₆) δppm 1212 3,4-Cl₂Ph— 2.25-2.33(4H, m), 2.92(3H, s), 3.36(2H, s), 3.42(4H, brs), 4.23(2H, s), 5.98(2H, s), 6.29-6.32(2H, m), 6.42-6.45(1H, m), 6.70-6.74(1H, m), 6.80-6.84(2H, m), 6.97(1H, d, J = 8.9 Hz), 7.11-7.17(1H, m), 7.84(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.16- 8.22(2H, m), 8.52(1H, d, J = 2.5 Hz), 10.55(1H, s). 1213 4-CF₃Ph— 2.26-2.33(4H, m), 2.92(3H, s), 3.37-3.41(6H, m), 4.23(2H, s), 5.98(2H, s), 6.29-6.34 (2H, m), 6.42-6.45(1H, m), 6.70-6.74(1H, m), 6.80-6.84(2H, m), 6.98(1H, d, J = 8.9 Hz), 7.11-7.17(1H, m), 7.93(2H, d, J = 8.3 Hz), 8.16(2H, d, J = 8.1 Hz), 8.21(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.54(1H, d, J = 2.3 Hz), 10.63(1H, s).

TABLE 265

Example No. R₈₂₂ R₈₂₃ Xb₂₂ M Form ¹H NMR (solvent) δppm 1214 —CH₃ piperonyl —N(CH₃)— 1 free (CDCl₃) 1.90(3H, s), 2.41-2.45(4H, m), 3.03(3H, s), 3.43(2H, s), 3.49(2H, brs), 3.63(2H, brs), 4.09 (2H, s), 4.77(2H, s), 5.95(2H, s), 6.70(2H, d, J = 9.1 Hz), 6.74-6.75(2H, m), 6.81-6.85(2H, m), 7.00(2H, d, J = 9.1 Hz), 7.04(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.24(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.31(1H, d, J = 2.1 Hz), 7.35(1H, d, J = 8.1 Hz), 7.83(1H, d, J = 2.6 Hz). 1215 —C₂H₅ piperonyl —N(CH₃)— 1 free (CDCl₃) 1.08 t, J = 7.4 Hz), 2.07(2H, q, J = 7.4 Hz), 2.41-2.45(4H, m), 3.03(3H, s), 3.43(2H, s), 3.48(2H, brs), 3.63(2H, brs), 4.09(2H, s), 4.77(2H, s), 5.95(2H, s), 6.70(2H, d, J = 9.2 Hz), 6.73-6.74(2H, m), 6.82(1H, d, J = 8.7 Hz), 6.85(1H, brs), 7.00(2H, d, J = 9.1 Hz), 7.04(1H, dd, J = 8.3 Hz, 2.0 Hz), 7,22(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.30(1H, d, J = 2.0 Hz), 7.34(1H, d, J = 8.3 Hz), 7.82(1H, d, J = 2.5 Hz). 1216 —CH₃ benzyl none 0 hydro- (DMSO-d₆) 1.87(3H, s), 3.14(2H, brs), chloride 3.37(6H, brs), 4.35(2H, s), 4.85(2H, s), 7.13(1H, d, J = 8.9 Hz), 7.22(2H, d, J = 8.4 Hz), 7.41-7.58(10H, m), 7.80(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.03(1H, d, J = 2.6 Hz), 10.88(1H, brs).

Example 1217 Production of 1H-indole-2-carboxylic acid {6-[4-(2,4-dioxothiazolidine-5-ylmethyl)-2-methylphenoxy]pyridin-3-yl}amide

To a solution of 5-[4-(5-aminopyridin-2-yloxy)-3-methylbenzyl]thiazolidine-2,4-dione (150 mg, 0.46 mmol) in DMF (5 mL) were added indole-2-carboxylic acid (74 mg, 0.46 mmol), 1-hydroxybenzotriazole monohydrate (70 mg, 0.46 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (110 mg, 0.57 mmol), and the resulting solution was stirred for 5 days at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was then purified by silica gel column chromatography (chloroform:methanol=30:1). To the obtained powdery substance was added ethanol, the resulting solution was filtered and the filtrate was washed with ethanol, to thereby yield 100 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.10 (3H, s), 3.09 (1H, dd, J=14.2 Hz, 9.7 Hz), 3.40 (1H, dd, J=14.2 Hz, 4.2 Hz), 4.94 (1H, dd, J=9.7 Hz, 4.2 Hz), 6.99 (1H, d, J=Hz), 7.04 (1H, d, J=8.9 Hz), 7.05-7.16 (2H, m), 7.20 (1H, s), 7.24 (18, dd, J=7.0 Hz, 1.0 Hz), 7.39 (1H, d, J=1.6 Hz), 7.46 (1H, d, J=8.2 Hz), 7.68 (1H, d, J=7.7 Hz), 8.21 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.49 (1H, d, J=2.8 Hz), 10.37 (1H, s), 11.80 (1H, s), 12.09 (1H, s).

The following compounds were produced in the same manner as in Example 1217.

TABLE 266

Example No. R₈₂₄ R₈₂₅ Form ¹H NMR (solvent) δppm 1218 3,4-(CH₃)₂Ph— 4-CH₃OPhCH₂— free (CDCl₃) 2.34(6H, s), 2.45(4H, brs), 3.45(2H, s), 3.47-3.79(4H, m), 3.81(3H, s), 6.83-6.89(2H, m), 6.97(1H, d, J = 8.9 Hz), 7.11-7.16(2H, m), 7.21-7.26(3H, m), 7.41-7.46(2H, m), 7.59-7.62 (1H, m), 7.67(1H, d, J = 1.9 Hz), 7.92(1H, brs), 8.23-8.30(1H, m), 8.31(1H, d, J = 2.4 Hz). 1219 2-(CH₃)₂NPh— benzyl trihydro- (DMSO-d₆) 3.07(6H, s), 3.17-3.48(8H, chloride m), 4.35(2H, s), 7.16-7.21(3H, m), 7.41-7.54(6H, m), 7.59-7.70(4H, m), 7.92(1H, d, J = 7.1 Hz), 8.27(1H, dd, J = Hz), 11.30(1H, s). 1220 3,5-(CH₃)₂Ph— benzyl hydro- (DMSO-d₆) 2.36(6H, s), 3.00-3.20(2H, chloride m), 3.20-3.40(2H, m), 3.47(2H, brs), 4.40(2H, brs), 4.33(2H, s), 7.13(1H, d, J = 8.9 Hz), 7.19(2H, d, J = 8.6 HO, 7.24(1H, s), 7.40-7.70(7H, m), 7.51(2H, d, J = 8.6 Hz), 8.26(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.56(1H, d, J = 2.6 Hz), 10.41(1H, s). 1221 2,3- benzyl hydro- (DMSO-d₆) 3.00-3.65(6H, m), 3.80(3H, (CH₃O)₂Ph— chloride s), 3.86(3H, s), 4.20(2H, brs), 4.33(2H, brs), 7.09-7.25(6H, m), 7.40-7.80(7H, m), 8.23(1H, dd, J = 8.9 Hz, 2.3 Hz), 8.52(1H, d, J = 2.3 Hz), 10.43(1H, s). 1222 4-(CH₃)₂NPh— benzyl free (CDCl₃) 2.48(4H, brs), 3.06(6H, s), 3.55(2H, s), 3.70(4H, brs), 6.71(2H, d, J = 9.0 Hz), 6.96(1H, d, J = 9.6 Hz), 7.13(2H, d, J = 8.7 Hz), 7.20-7.38(5H, m), 7.43(2H, d, J = 8.7 Hz), 7.71(1H, brs), 7.78(2H, d, J = 9.0 Hz), 8.20- 8.30(2H, m). 1223 1-naphthyl benzyl free (DMSO-d₆) 2.41(4H, brs), 3.51(4H, brs), 3.52 (2H, s), 7.17(3H, d, J = 8.7 Hz), 7.21-7.38(5H, m), 7.44(2H, d, J = 8.7 Hz), 7.55-7.69(3H, m), 7.80(1H, d, J = 6.4 Hz), 7.98-8.06(1H, m), 8.10 (1H, d, J = 8.1 Hz), 8.18-8.27(1H, m), 8.32(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.58(1H, d, J = 2.6 Hz), 10.76(1H, s).

TABLE 267

Example No. R₈₂₆ Form mp (° C.) 1224

maleate 172-175 1225

maleate 143-146 1226

free 187-189 1227

free 191-192 1228

maleate 180-182 1229 2,5-(CF₃)₂Ph— dihydrochloride 152-156 1230 2,5-F₂Ph— maleate 182-184 1231 2,3-Cl₂Ph— free 195-196 1232 3-PhOPh— free 171-172 1233 3-CF₃Ph— dihydrochloride 146-149

TABLE 268

Example No. R₈₂₇ R₈₂₈ R₈₂₉ R₈₃₀ MS (M⁺ + H) 1234 —H —H —H —H 532 1235 —H —H —OCH₃ —H 562 1236 —H —H —Cl —H 566 1237 —H —H —F —H 550 1238 —CH₃ —H —H —H 546 1239 —H —H —Br —H 612 1240 —H —H —CH₃ —H 546 1241 —H —H —OCF₃ —H 616 1242 —H —OCH₃ —H —H 562 1243 —H —Cl —H —H 566 1244 —H —H —H —OCH₃ 562 1245 —H —Cl —H —Cl 600 1246 —H —H —H —Cl 566 1247 —H —H —OCH₃ —OCH₃ 592

TABLE 269

Ex- ample MS No. R₈₃₁ R₈₃₂ R₈₃₃ R₈₃₄ R₈₃₅ M (M⁺ + H) 1248 —H —H —H —H —H 0 532 1249 —H —H —H —H —H 2 560 1250 —H —H —H —H —H 1 546 1251 —H —H —Cl —H —H 1 580 1252 —H —CH₃ —H —H —H 1 560 1253 —H —CH₃ —CH₃ —H —H 1 574 1254 —H —CH₃ —OCH₃ —H —H 1 590 1255 —H —CH₃ —F —H —H 1 578 1256 —H —CH₃ —C(CH₃)₃ —H —H 1 616 1257 —H —CH₃ —CH₃ —H —CH₃ 1 588 1258 —H —CH₃ —Br —H —F 1 658 1259 —H —CH₃ —H —H —F 1 578 1260 —H —CH₃ —C₂H₅ —H —H 1 588 1261 —H —H —F —H —H 1 564 1262 —H —H —H —F —H 1 564 1263 —CH₃ —H —H —H —H 1 560 1264 —H —H —OCH₃ —H —H 1 576 1265 —H —H —H —H —CH₃ 1 560 1266 —H —H —CH₃ —H —H 1 560 1267 —H —H —H —H —H 1 626

TABLE 270

Example No. R₈₃₆ ¹H NMR (solvent) δppm 1268 3-CNPh— (CDCl₃) 2.37-2.44(4H, m), 2.57-2.63(2H, m), 2.88-2.95(2H, m), 3.42-3.45(2H, m), 3.55(2H, s), 3.60-3.64(2H, m), 6.90(1H, d, J = 8.9 Hz), 7.00(2H, d, J = 8.6 Hz), 7.16(2H, d, J = 8.6 Hz), 7.25- 7.31(5H, m), 7.54-7.76(1H, m), 7.76-7.80(1H, m), 8.19-8.26(3H, m), 8.37(1H, d, J = 2.6 Hz), 9.41(1H, brs). 1269 2-CNPh— (CDCl₃) 2.35-2.45(4H, m), 2.60-2.66(2H, m), 2.95-3.01(2H, m), 3.40-3.44(2H, m), 3.52(2H, s), 3.63-3.67(2H, m), 7.05-7.13(3H, m), 7.23-7.32(8H, m), 7.69-7.80(3H, m), 7.93-7.96(2H, m), 8.23(1H, d, J = 2.5 Hz). 1270 3-N(CH₃)₂Ph— (CDCl₃) 2.35-2.44(4H, m), 2.57-2.62(2H, m), 2.91-2.98(8H, m), 3.39-3.43(2H, m), 3.53(2H, s), 3.62-3.65(2H, m), 6.84-6.92(2H, m), 7.02(2H, d, J = 8.6 Hz), 7.11(1H, d, J = 7.9 Hz), 7.19(2H, d, J = 8.6 Hz), 7.25-7.35(7H, m), 8.22-8.37 (3H, m). 1271 3-CH₃Ph— (CDCl₃) 2.36-2.46(7H, m), 2.57-2.63(2H, m), 2.91-2.97(2H, m), 3.40-3.44(2H, m), 3.56(2H, s), 3.62-3.66(2H, m), 6.91(1H, d, J = 8.9 Hz), 7.00-7.05(2H, m), 7.19(2H, d, J = 8.6 Hz), 7.25-7.35(7H, m), 7.66-7.71(2H, m), 8.23-8.31(2H, m), 8.43(1H, brs). 1272 3,4-(CH₃)₂Ph— (CDCl₃) 2.31(3H, s), 2.32(3H, s), 2.36-2.46(4H, m), 2.58-2.64(2H, m), 2.92-2.98 (2H, m), 3.41-3.44(2H, m), 3.56(2H, s), 3.63-3.67(2H, m), 6.90-6.94(1H, m), 7.03(2H, d, J = 8.4 Hz), 7.19-7.37(8H, m), 7.58-7.73(2H, m), 8.21-8.28(3H, m). 1273 2-FPh— (DMSO-d₆) 2.28-2.31(4H, m), 2.59-2.64(2H, m), 2.78-2.84(2H, m), 3.44-3.47 (6H, m), 7.01(2H, d, J = 8.4 Hz), 7.02-7.05(1H, m), 7.26(2H, d, J = 8.4 Hz), 7.31-7.40(7H, m), 7.51-7.61(1H, m), 7.64- 7.72(1H, m), 8.18(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.45(1H, d, J = 2.5 Hz), 10.54(1H, brs). 1274 3-FPh— (DMSO-d₆) 2.30(4H, brs), 2.62(2H, brs), 2.81(2H, brs), 3.47(6H, brs), 7.03(3H, brs), 7.25-7.30(7H, m), 7.47(1H, brs), 7.60(1H, d, J = 6.1 Hz), 7.77-7.81(2H, m), 8.20(1H, d, J = 7.6 Hz), 8.49(1H, brs), 10.46(1H, brs). 1275 4-FPh— (DMSO-d₆) 2.28-2.30(4H, m), 2.58-2.64(2H, m), 2.77-2.83(2H, m), 3.43-3.46 (6H, m), 7.00(2H, d, J = 8.6 Hz), 7.02(1H, d, J = 8.7 Hz), 7.25(2H, d, J = 8.6 Hz), 7.29-7.40(7H, m), 8.01-8.06(2H, m), 8.18(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.46(1H, d, J = 2.5 Hz), 10.39(1H, brs). 1276 4-AcPh— (DMSO-d₆) 2.28-2.32(4H, m), 2.59-2.65(5H, m), 2.79-2.84(2H, m), 3.44-3.47 (6H, m), 6.99-7.06(3H, m), 7.27-7.36(7H, m), 8.09(4H, brs), 8.21(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.50(1H, d, J = 2.6 Hz), 10.56(1H, brs). 1277 3,4-F₂Ph— (DMSO-d₆) 2.28-2.32(4H, m), 2.59-2.65(2H, m), 2.79-2.84(2H, m), 3.44-3.47 (6H, m), 7.01(2H, d, J = 8.4 Hz), 7.04(1H, d, J = 8.7 Hz), 7.27(2H, d, J = 8.4 Hz), 7.31-7.36(5H, m), 7.59-7.69(1H, m), 7.85- 7.89(1H, m), 8.00-8.07(1H, m), 8.18(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.46(1H, d, J = 2.5 Hz), 10.46(1H, brs).

TABLE 271

Example No. R₈₃₇ R₈₃₈ R₈₃₉ R₈₄₀ R₈₄₁ ¹H NMR (solvent) δppm or MS 1278 —H —F —H —F —H ¹H NMR (DMSO-d₆) 2.29- 2.32(4H, m), 2.59-2.65(2H, m), 2.79-2.85(2H, m), 3.44-3.48(6H, m), 7.00-7.06(3H, m), 7.25- 7.36(7H, m), 7.51-7.59(1H, m), 7.67-7.71(2H, m), 8.19(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.48(1H, d, J = 2.5 Hz) 10.51(1H, brs). 1279 —H —H —SO₂NH₂ —H —H ¹H NMR, (DMSO-d₆) 2.25- 2.35(4H, m), 2.60-2.66(2H, m), 2.74-2.85(2H, m), 3.31 (2H, s), 3.40-3.50(4H, m), 7.00-7.06(3H, m), 7.25-7.34(7H, m), 7.53(2H, s), 7.97 (2H, d, J = 8.6 Hz), 8.12(2H, d, J = 8.6 Hz), 8.21(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.49 (1H, d, J = 2.7 Hz), 10.56(1H, s). 1280 —H —H —NHAc —H —H MS 576(M⁺ − 1) 1281 —F —H —CF₃ —H —H MS 607(M⁺ + H) 1282 —COOC₂H₅ —H —H —H —H MS 593(M⁺ + 1) 1283 —Cl —Cl —H —H —H MS 590(M⁺ + 2) 1284 —H —H —COOCH₃ —H —H MS 579(M⁺ + H) 1285 —OCH₃ —H —OCH₃ —H —H MS 580(M⁺) 1286 —Cl —H —Cl —H —H MS 589(M⁺) 1287 —CH₃ —H —CH₃ —H —H MS 548(M⁺) 1288 —F —H —F —H —H MS 557(M⁺ + H) 1289 —H —OCH₃ —OCH₃ —H —H MS 580(M⁺) 1290 —CF₃ —H —H —H —H MS 589(M⁺ + 1) 1291 —H —CF₃ —H —H —H MS 588(M⁺) 1292 —H —COOCH₃ —H —H —H MS 579(M⁺ + 1) 1293 —F —H —H —H —F MS 557(M⁺ + 1) 1294 —F —F —H —H —H MS 557(M⁺ + H) 1295 —CF₃ —H —H —CF₃ —H MS 656(M⁺) 1296 —H —F —H —CF₃ —H MS 606(M⁺) 1297 —F —CF₃ —H —H —H MS 607(M⁺ + H) 1298 —F —H —H —CF₃ —H MS 607(M⁺ + 1) 1299 —CH₃ —H —H —CH₃ —H MS 549(M⁺ + 1) 1300 —F —H —H —F —H MS 557(M⁺ + H) 1301 —Cl —H —F —H —H MS 572(M⁺) 1302 —H —OAc —H —H —H MS 579(M⁺ + 1) 1303 —OCF₃ —H —H —H —H MS 604(M⁺)

TABLE 272

Example No. R₈₄₂ R₈₄₃ R₈₄₄ R₈₄₅ R₈₄₆ ¹H NMR or MS 1304 —H —CF₃ —F —H —H MS 607(M⁺ + 1) 1305 —OCH₃ —H —H —OCH₃ —H MS 580(M⁺) 1306 —Cl —H —H —Cl —H MS 590(M⁺ + 1) 1307 —CH₃ —H —H —F —H MS 552(M⁺) 1308 —N(CH₃)₂ —H —H —H —H MS 564(M⁺ + H) 1309 —OCH₃ —H —H —H —OCH₃ MS 581(M⁺ + H) 1310 —H —OPh —H —H —H MS 630(M⁺ + H) 1311 —H —OCH₃ —H —OCH₃ —H MS 581(M⁺ + H) 1312 —H —Cl —H —Cl —H MS 589(M⁺ + H) 1313 —H —CH₃ —H —CH₃ —H MS 549(M⁺ + H) 1314 —OCH₃ —OCH₃ —H —H —H MS 581(M⁺ + H) 1315 —CH₃ —CH₃ —H —H —H MS 549(M⁺ + H) 1316 —CH₃ —F —H —H —H MS 553(M⁺ + H) 1317 —H —H —N(CH₃)₂ —H —H MS 564(M⁺ + H) 1318 —H —CF₃ —H —CF₃ —H MS 656(M⁺) 1319 —Cl —H —H —CF₃ —H MS 622(M⁺) 1320 —H —CH₃ —NHAc —H —H MS 591(M⁺) 1321 —H —Cl —NHAc —H —H MS 611(M⁺) 1322 —H —OCH₃ —NHAc —H —H MS 607(M⁺) 1323 —H —NHAc —CH₃ —H —H MS 591(M⁺) 1324 —H —NHAc —Cl —H —H MS 611(M⁺) 1325 —H —NHAc —OCH₃ —H —H MS 607(M⁺) 1326 —H —NHAc —F —H —H MS 595(M⁺) 1327 —H —CH₃ —NHCOPh —H —H MS 653(M⁺) 1328 —H —Cl —NHCOPh —H —H MS 673(M⁺) 1329 —H —OCH₃ —NHCOPh —H —H MS 669(M⁺) 1330 —H —NHCOPh —CH₃ —H —H MS 653(M⁺) 1331 —H —NHCOPh —Cl —H —H MS 673(M⁺) 1332 —H —NHCOPh —OCH₃ —H —H MS 669(M⁺) 1333 —H —NHCOPh —F —H —H MS 657(M⁺) 1334 —COOH —H —Cl —Cl —H ¹H NMR (DMSO-d₆) δ 2.42(4H, brs), 2.62(2H, t, J = 7.1 Hz), 2.81(2H, t, J = 7.1 Hz), 3.33(1H, brs), 3.47(4H, brs), 3.60(2H, s), 7.00(2H, d, J = 8.6 Hz), 7.02(1H, d, J = 4.7 Hz), 7.26(2H, d, J = 8.6 Hz), 7.28-7.38(5H, m), 7.94(1H, s), 8.05(1H, s), 8.10(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.36(1H, d, J = 2.8 Hz), 10.68(1H, s).

TABLE 273

Ex- ample No. R₈₄₇ R₈₄₈ R₈₄₉ R₈₅₀ R₈₅₁ MS 1335 —H —H —H —H —H 546(M⁺) 1336 —H —OCH₃ —H —H —H 577(M⁺ + H) 1337 —Cl —H —H —H —H 581(M⁺ + H) 1338 —H —Cl —H —H —H 581(M⁺ + H) 1339 —H —H —Cl —H —H 581(M⁺ + H) 1340 —F —H —H —H —H 565(M⁺ + H) 1341 —H —F —H —H —H 565(M⁺ + H) 1342 —H —H —F —H —H 565(M⁺ + H) 1343 —H —H —N(CH₃)₂ —H —H 590(M⁺ + 1) 1344 —H —OCH₃ —OCH₃ —H —H 606(M⁺) 1345 —Cl —H —H —H —Cl 615(M⁺ + 1) 1346 —H —Cl —Cl —H —H 615(M⁺ + H) 1347 —F —H —H —H —F 583(M⁺ + H) 1348 —H —F —H —F —H 583(M⁺ + H) 1349 —H —OCH₂O— —H —H 591(M⁺ + H) 1350 —H —OCH₃ —H —OCH₃ —H 607(M⁺ + H) 1351 —H —H —CH₃ —H —H 561(M⁺ + H) 1352 —H —CF₃ —H —H —H 615(M⁺ + H) 1353 —H —H —OCH₃ —H —H 577(M⁺ + 1) 1354 —OCH₃ —OCH₃ —H —H —H 606(M⁺) 1355 —OCH₃ —H —H —OCH₃ —H 607(M⁺ + 1) 1356 —H —OCH₃ —OCH₃ —OCH₃ —H 637(M⁺ + 1)

TABLE 274

Example No. R₈₅₂ ¹H NMR (solvent) δppm 1357

(CDCl₃) 1.68-1.86(2H, m), 1.91-2.03(2H, m), 2.12(3H, s), 2.34- 2.40(2H, m), 2.40-2.46(2H, m), 2.48-2.56(1H, m), 2.62(2H, t, J = 7.9 Hz), 2.66-2.75(1H, m), 2.96(2H, t, J = 7.9 Hz), 3.08- 3.18(1H, m), 3.38-3.45(2H, m), 3.51(2H, s), 3.59-3.69(2H, m), 3.88-3.97(1H, m), 4.59-4.69(1H, m), 6.89(1H, d, J = 9.7 Hz), 7.02(2H, d, J = 8.4 Hz), 7.22(2H, d, J = 8.4 Hz), 7.25-7.31(1H, m), 7.31-7.38(4H, m), 7.54(1H, brs), 8.08-8.16(2H, m). 1358

(CDCl₃) 2.05-2.18(1H, m), 2.32-2.40(2H, m), 2.40-2.47(2H, m), 2.49-2.56 (1H, m), 2.63(2H, t, J = 7.9 Hz), 2.80-2.90(1H, m), 2.90-3.02(3H, m), 3.36-3.46(2H, m), 3.51(2H, s), 3.60-3.70(2H, m), 4.64-4.70(1H, m), 6.88-7.02(3H, m), 7.04(2H, d, J = 8.4 Hz), 7.09-7.15(1H, m), 7.15-7.22(1H, m), 7.22-7.25(1H, m), 7.25-7.30(2H, m), 7.30-7.38(4H, m), 8.14(1H, dd, J = 8.8, 2.8 Hz), 8.25(1H, d, J = 2.8 Hz), 8.54(1H, brs). 1359 —CH₂OCH₃ (CDCl₃) 2.30-2.38(21, m), 2.38-2.45(2H, m), 2.62(2H, t, J = 7.9 Hz), 2.96 (2H, t, J = 7.9 Hz), 3.35-3.43(2H, m), 3.50(2H, s), 3.52(3H, s), 3.58-3.68(2H, m), 4.04(2H, s), 6.90(1H, d, J = 8.8 Hz), 7.03(2H, d, J = 8.4 Hz), 7.22(2H, d, J = 8.4 Hz), 7.25- 7.29(1H, m), 7.29-7.37(4H, m), 8.14(1H, dd, J = 8.8, 2.8 Hz), 8.18-8.25(2H, m). 1360 —CH₃ (CDCl₃) 2.18(3H, s), 2.32-2.39(2H, m), 2.39-2.45(2H, m), 2.61(2H, t, J = 7.9 Hz), 2.95(2H, t, J = 7.9 Hz), 3.36-3.44(2H, m), 3.50(2H, s), 3.60-3.68(2H, m), 6.85-6.92(1H, m), 7.02(2H, d, J = 8.4 Hz), 7.21(2H, d, J = 8.4 Hz), 7.25-7.30(1H, m), 7.30- 7.35(4H, m), 7.38(1H, brs), 8.06-8.15(2H, m). 1361 —C(CH₃)₃ (CDCl₃) 1.32(9H, s), 2.32-2.38(2H, m), 2.38-2.44(2H, m), 2.62(2H, t, J = 7.9 Hz), 2.96(2H, t, J = 7.9 Hz), 3.37-3.43(2H, m), 3.50(2H, s), 3.60-3.69(2H, m), 6.87(1H, d, J = 9.8 Hz), 7.02(2H, d, J = 8.4 Hz), 7.22(2H, d, J = 8.4 Hz), 7.25-7.30(1H, m), 7.30-7.37(5H, m), 8.07-8.15(2H, m). 1362 —(CH₂)₂OPh (DMSO-d₆) 2.23-2.33(4H, m), 2.56-2.67(2H, m), 2.73-2.86(4H, m), 3.37-3.50(6H, m), 4.26(2H, t, J = 6.0 Hz), 6.90-6.96(3H, m), 6.96-7.02(3H, m), 7.20-7.35(9H, m), 8.07(1H, dd, J = 8.8, 2.7 Hz), 8.33(1H, d, J = 2.7 Hz) 10.23(1H, s). 1363 3-CH₃OPhOCH₂— (DMSO-d₆) 2.23-2.34(4H, m), 2.58-2.68(2H, m), 2.76-2.85(2H, m), 3.38-3.50(6H, m), 3.74(3H, s), 4.68(2H, s), 6.51-6.62(3H, m), 6.95-7.04(3H, m), 7.18-7.28(4H, m), 7.28-7.37(4H, m), 8.09(1H, dd, J = 8.9, 2.7 Hz), 8.36 (1H, d, J = 2.7 Hz), 10.22(1H, s). 1364 3-CH₃PhOCH₂— (DMSO-d₆) 2.23-2.34(7H, m), 2.56-2.66(2H, m), 2.74-2.84(2H, m), 3.37-3.50(6H, m), 4.67(2H, s), 6.75-6.81(2H, m), 6.81- 6.88(1H, m), 6.96-7.03(3H, m), 7.14-7.21(1H, m), 7.21-7.28(3H, m), 7.28-7.36(4H, m), 8.09(1H, dd, J = 8.9, 2.7 Hz), 8.36(1H, d, J = 2.7 Hz), 10.21(1H, s). 1365 4-CH₃PhOCH₂— (DMSO-d₆) 2.23(3H, s), 2.26-2.32(4H, m), 2.57-2.65(2H, m), 2.73-2.83(2H, m), 3.36-3.50(6H, m), 4.65(2H, s), 6.90(2H, d, J = 8.5 Hz), 6.95-7.02(3H, m), 7.11(2H, d, J = 8.5 Hz),7.20- 7.29(3H, m), 7.29-7.35(4H, m), 8.08(1H, dd, J = 8.9, 2.7 Hz), 8.36(1H, d, J = 2.7 Hz), 10.21(1H, s).

TABLE 275

Example No. R₈₅₃ ¹H NMR (DMSO-d₆) δppm or MS 1366 PhOCH₂— ¹H NMR 2.23-2.34(4H, m), 2.57-2.65(2H, m), 2.76- 2.85(2H, m), 3.38-3.50(6H, m), 4.70(2H, s), 6.92- 7.05(6H, m), 7.20-7.27(3H, m), 7.27-7.38(6H, m), 8.09(1H, dd, J = 8.9, 2.7 Hz), 8.36(1H, d, J = 2.7 Hz), 10.24(1H, s). 1367 4-CH₃PhCH₂— ¹H NMR 2.21-2.32(7H, m), 2.56-2.65(2H, m), 2.73- 2.82(2H, m), 3.37-3.49(6H, m), 3.58(2H, s), 6.92- 7.00(3H, m), 7.09-7.16(2H, m), 7.19-7.21(2H, m), 7.21- 7.27(3H, m), 7.27-7.35(4H, m), 8.04(1H, dd, J = 8.9, 2.7 Hz), 8.30(1H, d, J = 2.7 Hz). 10.27(1H, s). 1368 4-ClPhCH₂— ¹H NMR 2.21-2.32(4H, m), 2.55-2.65(2H, m), 2.73- 2.82(2H, m), 3.38-3.49(6H, m), 3.66(2H, s), 6.93- 7.00(3H, m), 7.20-7.26(3H, m), 7.26-7.35(6H, m), 7.35- 7.42(2H, m), 8.04(1H, dd, J = 8.9, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 10.33(1H, s). 1369 4-CH₃OPhCH₂— ¹H NMR 2.22-2.33(4H, m), 2.56-2.65(2H, m), 2.75- 2.83(2H, m), 3.38-3.50(6H, m), 3.56(2H, s), 3.73(3H, s), 6.84-6.90(2H, m), 6.92-7.00 (3H, m), 7.19-7.28(5H, m), 7.28-7.36(4H, m), 8.04(1H, dd, J = 8.9, 2.7 Hz), 8.30(1H, d, J = 2.7 Hz), 10.25(1H, s). 1370 4-FPhCH₂— ¹H NMR 2.23-2.32(4H, m), 2.56-2.65(2H, m), 2.75- 2.84(2H, m), 3.39-3.50(6H, m), 3.64(2H, s), 6,93- 7.00(3H, m), 7.11-7.19(2H, m), 7.21-7.29(3H, m), 7.29- 7.40(6H, m), 8.04(1H, dd, J = 8.9, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 10.31(1H, s). 1371 benzyl ¹H NMR 2.22-2.33(4H, m), 2.56-2.67(2H, m), 2.72- 2.84(2H, m), 3.37-3.50(6H, m), 3.64(2H, s), 6.90- 7.00(3H, m), 7.20-7.29(4H, m), 7.29-7.38(8H, m), 8.05(1H, dd, J = 8.8, 2.7 Hz), 8.31(1H, d, J = 2.7 Hz), 10.32(1H, s). 1372 —(CH₂)₃Ph MS 563(M⁺ + 1) 1373 —(CH₂)₂CH₃ MS 487(M⁺ + 1) 1374 —CH(CH₃)₂ MS 486(M⁺) 1375 cyclopentyl MS 512(M⁺) 1376

MS 630(M⁺) 1377 —(CH₂)₂Ph MS 549(M⁺ + H) 1378 2-furyl MS 511(M⁺ + H) 1379 2-thienyl MS 527(M⁺ + H) 1380 2-thenyl MS 541(M⁺ + H) 1381 cyclohexyl MS 527(M⁺ + H) 1382 cycloheptyl MS 541(M⁺ + H) 1383 cyclopentylmethyl MS 527(M⁺ + H) 1384 cyclohexylmethyl MS 541(M⁺ + H) 1385 2-CH₃OPhOCH₂— MS 581(M⁺ + 1)

TABLE 276

Example No. R₈₅₄ MS 1386

581(M⁺ + 1) 1387

582(M⁺ + 1) 1388

587(M⁺ + H) 1389

547(M⁺) 1390

547(M⁺) 1391

561(M⁺ + 1) 1392 2-CH₃PhOCH₂— 565(M⁺ + H) 1393 2-ClPhOCH₂— 585(M⁺) 1394 3-ClPhOCH₂— 585(M⁺ + H) 1395 4-CNPhOCH₂— 575(M⁺) 1396

595(M⁺ + H) 1397 3,4,5-(CH₃O)₃PhOCH₂— 641(M⁺ + 1) 1398

556(M⁺ + 1) 1399

556(M⁺ + H) 1400

590(M⁺ + H) 1401

567(M⁺) 1402

556(M⁺)

TABLE 277

Example No. R₈₅₅ MS 1403

566(M⁺ − 1) 1404

559(M⁺) 1405

562(M⁺ + H) 1406

528(M⁺ + 1) 1407 2-quinolyl 571(M⁺) 1408 3-quinolyl 572(M⁺ + H) 1409 4-quinolyl 571(M⁺) 1410 6-quinolyl 571(M⁺) 1411 1-isoquinolyl 571(M⁺) 1412 3-isoquinolyl 572(M⁺ + H) 1413

560(M⁺) 1414

590(M⁺) 1415 3,4-Cl₂PhCH₂— 603(M⁺ + H) 1416 2-CH₃OPhCH₂— 564(M⁺) 1417 —CH(CH₂Ph)NHAc 605(M⁺) 1418

557(M⁺) 1419 —CH₂NHAc 515(M⁺) 1420 —CH(CH₃)NHAc 529(M⁺) 1421 —CH(CH₂Ph)NHCOPh 667(M⁺) 1422

619(M⁺) 1423 —CH₂NHCOPh 577(M⁺)

TABLE 278

Example No. R₈₅₆ MS 1424 —CH(CH₃)NHCOPh 591(M⁺) 1425 2-pyridyl 522(M⁺ + H) 1426 3-pyridyl 522(M⁺ + H) 1427 4-pyridyl 522(M⁺ + H) 1428 1-naphthyl 571(M⁺ + H) 1429

551(M⁺) 1430 2-pyrrolyl 509(M⁺) 1431 3-pyridylmethyl 536(M⁺ + H) 1432 3-furyl 510(M⁺) 1433 3-thienyl 526(M⁺) 1434 3-thenyl 541(M⁺ + H) 1435

592(M⁺) 1436 3-CH₃PhCH₂— 549(M⁺ + H) 1437 3-ClPhCH₂— 569(M⁺ + H) 1438 2-FPhCH₂— 553(M⁺ + H) 1439 3-FPhCH₂— 553(M⁺ + H) 1440 2,5-(CH₃O)₂PhCH₂— 594(M⁺) 1441 2,4-Cl₂PhCH₂— 603(M⁺ + H) 1442 2,6-Cl₂PhCH₂— 602(M⁺) 1443 3,4,5-(CH₃O)₃PhCH₂— 624(M⁺) 1444 —CH(OCH₃)Ph 564(M⁺) 1445

622(M⁺) 1446

588(M⁺ + H) 1447

659(M⁺) 1448

589(M⁺)

TABLE 279

Example No. R₈₅₇ MS 1449

589(M⁺) 1450

590(M⁺ + H) 1451

573(M⁺ + H) 1452 4-CH₃OPhO(CH₂)₂— 595(M⁺ + H) 1453 4-CH₂OPh(CH₂)₂— 579(M⁺ + H) 1454 3,4,5-(CH₃O)₃Ph(CH₂)₂— 638(M⁺) 1455 2,4-Cl₂PhOCH₂— 618(M⁺) 1456 PhSCH₂— 567(M⁺ + H) 1457 —(CH₂)₂COPh 577(M⁺ + H) 1458

573(M⁺) 1459

588(M⁺ + H) 1460

590(M⁺ + H) 1461

594(M⁺ + H) 1462

578(M⁺ + H) 1463

573(M⁺) 1464 4-CH₃OPh(CH₂)₃— 593(M⁺ + H) 1465

576(M⁺)

TABLE 280

Example No. R₈₅₈ mp (° C.) or ¹H NMR (DMSO-d₆) δppm 1466 2,5-F₂Ph— mp 173-176 1467

mp 181-182 1468

mp 199-201 1469 2,3-Cl₂Ph— mp 149-151 1470 2,4-Cl₂Ph— ¹H NMR 2.54(4H, brs), 2.64(2H, t, J = 7.5 Hz), 2.81(2H, t, J = 7.5 Hz), 3.51 (4H, brs), 3.65(2H, brs), 6.01(2H, s), 6.81(1H, d, J = 8.0 Hz), 6.89(1H, d, J = 8.0 Hz), 6.92(1H, s), 7.01(2H, d, J = 8.5 Hz), 7.04(1H, d, J = 9.0 Hz), 7.26(2H, d, J = 8.5 Hz), 7.57(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.65(1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 2.0 Hz), 8.15(1H, dd, J = 9.0 Hz, 2.5 Hz) 8.41(1H, d, J = 2.5 Hz), 10.69(1H, s). 1471 2,5-(CF₃)₂Ph— ¹H NMR 2.54(4H, brs), 2.64(2H, t, J = 7.5 Hz), 2.81(2H, t, J = 7.5 Hz), 3.49 (4H, brs), 3.59(2H, brs), 6.00(2H, s), 6.79(1H, d, J = 8.0 Hz), 6.88(1H, d, J = 8.0 Hz), 6.90(1H, s), 7.02(2H, d, J = 8.5 Hz), 7.05(1H, d, J = 9.0 Hz), 7.27(2H, d, J = 8.5 Hz), 8.12-8.14(3H, m), 8.21(1H, s), 8.37(1H, d, J = 2.5 Hz), 10.84 (1H, s). 1472 3-CF₃Ph— ¹H NMR 2.54(4H, brs), 2.64(2H, t, J = 7.5 Hz), 2.82(2H, t, J = 7.5 Hz), 3.51 (4H, brs), 3.63(2H, brs), 6.01(2H, s), 6 81(1H, d, J = 8.0 Hz), 6.89(1H, d, J = 8.0 Hz), 6.92(1H, s), 7.02(2H, d, J = 8.5 Hz), 7.05(1H, d, J = 9.0 Hz), 7.27(2H, d, J = 8.5 Hz), 7.80(1H, t, J = 8.0 Hz), 7.99(1H, d, J = 8.0 Hz), 8.19(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.27(1H, d, J = 8.0 Hz), 8.30(1H, s), 8.48(1H, d, J = 2.5 Hz), 10.61(1H, s). 1473 2,3-F₂Ph— ¹H NMR 2.54(4H, brs), 2.64(2H, t, J = 7.5 Hz), 2.81(2H, t, J = 7.5 Hz), 3.51 (4H, brs), 3.62(2H, brs), 6.01(2H, s), 6.80(1H, d, J = 8.0 Hz), 6.89(1H, d, J = 8.0 Hz), 6.92(1H, s), 7.02(2H, d, J = 8.5 Hz), 7.04(1H, d, J = 9.0 Hz), 7.26(2H, d, J = 8.5 Hz), 7.36(1H, m), 7.50(1H, m), 7.60(1H, m), 8.16(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.43(1H, d, J = 2.5 Hz), 10.67(1H, s).

TABLE 281

Example No. R₈₅₉ Xb₂₃ Form mp (° C.) or ¹H NMR (solvent) δppm 1474

—N(Ac)— free mp 142-144 1475 3,4-F₂Ph— —CH₂— free ¹H NMR (CDCl₃) 2.31-2.40(4H, m), 2.59- 2.65(2H, m), 2.92-2.98(2H, m), 3.38-3.41(4H, m), 3.60-3.64(2H, m), 5.94(2H, s), 6.70- 6.77(2H, m), 6.84(1H, s), 6.94(1H, d, J = 8.9 Hz), 7.01-7.07(2H, m), 7.19-7.24(2H, m), 7.29-7.33 (1H, m), 7.62-7.68(1H, m), 7.74- 7.81(1H, m), 8.01(1H, brs), 8.16-8.20(1H, m), 8.24(1H, d, J = 2.2 Hz). 1476

—CH₂— hydro- chloride ¹H NMR (DMSO-d₆) 2.60-2.98(6H, m), 3.01- 3.15(1H, m), 3.26(2H, t, J = 15.0 Hz), 3.46- 3.59(1H, m), 4.00-4.11(1H, m), 4.15-4.27(2H, m), 4.30-4.51(1H, m), 6.05(2H, s), 6.97 (1H, d, J = 7.9 Hz), 6.98-7.09(4H, m), 7.20- 7.31(3H, m), 7.97(1H, d, J = 8.4 Hz), 8.11- 8.23(3H, m), 8.50(1H, d, J = 2.7 Hz), 10.78(1H, s), 11.38(1H, brs). 1477

—CH₂— hydro- chloride ¹H NMR (DMSO-d₆) 2.60-2.99(6H, m), 3.01- 3.17(1H, m), 3.25(2H, t, J = 15.0 Hz), 3.48- 3.60(1H, m), 4.00-4.12(1H, m), 4.15-4.28(2H, m), 4.39-4.51(1H, m), 6.05(2H, s), 6.96 (1H, d, J = 8.8 Hz), 6.99-7.08(4H, m), 7.19- 7.31(3H, m), 7.55(1H, t, J = 7.8 Hz), 7.90- 8.04(2H, m), 8.16(1H, dd, J = 8.8 Hz, 2.7 Hz), 8.43(1H, d, J = 2.7 Hz), 10.82(1H, s), 11.44(1H, brs). 1478

—CH₂— hydro- chloride mp 213-215 1479

—CH₂— trihydro- chloride ¹H NMR (DMSO-d₆) 2.69-3.40(15H, m), 3.99- 4.49(5H, m), 6.07(2H, s), 6.97-7.09(5H, m), 7.21-7.30(3H, m), 7.43-7.47(1H, m), 7.65- 7.70(2H, m), 7.91(1H, d, J = 9.4 Hz), 8.21(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.48(1H, d, J = 2.1 Hz), 11.23(1H, s). 1480 3-PhOPh— —CH₂— hydro- ¹H NMR (DMSO-d₆) 2.60-3.09(7H, m). 3.18- chloride 3.31(2H, m), 3.38-3.50(1H, m), 4.08(1H, d, J = 14.0 Hz), 4.22(2H, brs), 4.45(1H, d, J = 14.0 Hz), 6.07(2H, s), 6.90-7.08(7H, m), 7.15- 7.26(5H,m), 7.44(2H, t, J = 7.9 Hz), 7.56(1H, t, J = 7.9 Hz), 7.61(1H, s), 7.79(1H, d, J = 7.6 Hz), 8.19(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.45(1H, d, J = 2.6 Hz), 10.45(1H, s), 10.90- 11.20(1H, m).

TABLE 282

Example No. R₈₆₀ R₈₆₁ Xb₂₄ Form mp (°C) or ¹H NMR (solvent) δppm 1481 1-naphthyl —H —CH₂— hydrochloride ¹H NMR (DMSO-d₆) 2.50-3.60(10H, m), 4.00-4.20(1H, m), 4.22(2H, s), 4.35-4.51(1H, m), 6.07(2H, s), 6.91-7.08(2H, m), 7.04(2H, d, J = 8.6 Hz), 7.08(1H, d, J = 8.9 Hz), 7.21(1H, s), 7.39 (2H, d, J = 8.6 Hz), 7.55-7.67(3H, m), 7.79(1H, d, J = 7.1 Hz), 7.98-8.05(1H, m), 8.10 (1H, d, J = 8.2 Hz), 8.16-8.22(1H, m), 8.26(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.54(1H, d, J = 2.5 Hz), 10.72(1H, s) 1482

—CH₃ —N(CH₃)— free ¹H NMR (CDCl₃) 2.13(3H, s), 2.43(4H, t, J = 4.8 Hz), 3.01(3H, s), 3.44(2H, s), 3.45-3.56 (2H, m), 3.56-3.70(2H, m), 4.08(2H, s), 4.09(3H, s), 5.95(2H, s), 6.51-6.60(2H, m), 6.72-6.76(2H, m), 6.82(1H, d, J = 8.9 Hz), 6.85(1H, s), 6.92(1H, d, J = 8.4 Hz), 7.04(1H, s), 7.14-7.23(1H, m), 7.28-7.40(1H, m), 7.42 (1H, d, J = 7.9 Hz), 7.67(1H, d, J = 7.9 Hz), 7.94(1H, s), 8.14(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, d, J = 2.8 Hz). 1483 3,5-(CH₃)₂Ph— —H —CH₂— hydrochloride H NMR (DMSO-d₆) 2.36(6H, s), 2.60-3.60 (10H, m), 4.00-4.60(2H, m), 4.29(2H, s), 6.07 (2H, s), 6.85-7.10(5H, m), 7.22(2H, s), 7.27 (2H, d, J = 8.5 Hz), 7.57(2H, s), 7.27 (2H, d, J = 8.5 Hz), 7.57(2H, s), 8.19 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.48(1H, d, J = 2.7 Hz), 10.34(1H, s). 1484

—CH₃ —N(CH₃)— free mp 143-144   1485

—CH₃ —N(CH₃)— free mp 163-165   1486

—CH₃ —N(CH₃)— free mp 224-227 dec 1487

—CH₃— —N(CH₃)— free mp 131-134  

TABLE 283

Example No. R₈₆₂ R₈₆₃ Xb₂₅ Form ¹H NMR (solvent) δppm 1488 2,3-(CH₃O)₂Ph— —H —CH₂— hydrochloride (DMSO-d₆) 3.80(3H, s), 3.86(3H, s), 2.60-3.60(10H, m), 4.00-4.20(1H, m), 4.22(2H, s), 4.40-4.55(1H, m), 6.07(2H, s), 6.90-7.30(11H, m), 8.18(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.45(1H, d, J = 2.6 Hz), 10.37(1H, s). 1489

—CH₃— —N(CH₃)— free (CDCl₃) 2.12(3H, s), 2.35-2.50(4H, m), 3.01(3H, s), 3.43(2H, s), 3.45-3.55(2H, m), 3.57-3.70(2H, m), 4.07 (2H, s), 5.95(2H, s), 6.40(2H, t, J = 2.2 Hz), 6.50-6.5 9(2H, m), 6.74(2H, s), 6.81(1H, d, J = 8.9 Hz), 6.85(1H, s), 6.92(1H, d, J = 8.6 Hz), 7.17(2H, t, J = 2.2 Hz), 7.49(2H, d, J = 8.8 Hz), 7.90(1H, brs), 7.95(2H, d, J = 8.8 Hz), 7.90(1H, brs), 7.95(2H, d, J = 8.8 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.3 Hz), 8.22(1H, d, J = 2.3 Hz). 1490

—CH₃ —N(CH₃)— free (CDCl₃) 2.04(3H, s), 2.39-2.46(4H, m), 2.94(3H, s), 3.43-3.51(4H, m), 3.59-3.63(2H, m), 4.05(2H, s), 5.94 (2H, s), 6.41-6.48(2H, m), 6.67-6.84(6H, m), 7.44(1H, d, J = 4.1 Hz), 8.01(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.17 (1H, d, J = 2.6 Hz), 8.82(1H, brs). 1491

—CH₃ —N(CH₃)— maleate (DMSO-d₆) 2.01(3H, s), 2.50(4H, brs), 2.93(3H, s), 3.33(4H, brs), 4.03(2H, s), 4.29(2H, s), 6.06(2H, s), 6.10(2H, s), 6.48(1H, dd, J = 8.9 Hz, 2.8 Hz), 6.56(1H, s), 6.81-7.01(6H, m), 7.43-7.53(2H, m), 7.57(1H, dd, J = 5.9 Hz, 3.6 Hz), 7.77(1H, dd, J = 5.8 Hz, 3.6 Hz), 7.88(1H, d, J = 15.7 Hz), 8.11(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.36(1H, d, J = 2.6 Hz), 10.42(1H, s). 1492  4-(CH₃)₂NPh— —H —CH₂— free (CDCl₃) 2.33(2H, t, J = 5.0 Hz), 2.39(2H, t, J = 5.0 Hz), 2.61(2H, t, J = 7.5 Hz), 2.97(2H, t, J = 7.5 Hz), 3.05(6H, s), 3.32-3.45(2H, m), 3.41(2H, s), 3.63(2H, t, J = 5.0 Hz), 5.94(2H, s), 6.70(2H, d, J = 9.0 Hz), 6.74 (2H, s), 6.85(1H, s), 6.92(1H, d, J = 9.0 Hz), 7.04(2H, d, J = 8.6 Hz), 7.22(2H, d, J = 8.6 Hz), 7.72(1H, s), 7.78(2H, d, J = 9.0 Hz), 8.21(1H, d, J = 2.8 Hz), 8.23 (1H, dd, J = 8.6 Hz, 2.8 Hz). 1493 2,4-Cl₂PhOCH₂— —CH₃ —N(CH₃)— free (CDCl₃) 2.11(3H, s), 2.42(4H, brs), 3.00(3H, s), 3.43 (2H, s), 3.49(2H, brs), 3.63(2H, brs), 4.07(2H, s), 4.62 (2H, s), 5.94(2H, s), 6.54(1H, dd, J = 11.1 Hz, 2.3 Hz), 6.74-6.92(6H, m), 7.24(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.43(1H, d, J = 2.5 Hz), 8.06(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.23(1H, d, J = 2.6 Hz), 8.55(1H, s).

TABLE 284

Example No. R₈₆₄ R₈₆₅ Xb₂₆ Xb₂₇ Form mp (°C) or ¹H NMR (solvent) δppm 1494

—CH₃ —N(CH₃)— —CH₂— free ¹H NMR (CDCl₃) 2.10(3H, s), 2.45(4H, brs), 3.01(3H, s), 3.45(2H, s), 3.51 (2H, brs), 3.64(2H, brs), 4.08(2H, s), 5.95 (2H, s), 6.51- 6.59(3H, m), 6.75-6.92 (5H, m), 7.33(1H, d, J = 8.3 Hz), 7.45 (1H, d, J = 8.4 Hz), 7.61- 7.76(3H, m), 8.16(1H, d, J = 8.9 Hz), 8.18(1H, s). 1495

—CH₃ —N(CH3)— —CH₂— free ¹H NMR (CDCl₃) 2.09(3H, s), 2.34-2.48 (4H, m), 2.98(3H, s), 3.42(2H, s), 3.40- 3.55(2H, m), 3.55-3.70(2H, m), 3.84(3H, s), 4.06(2H, s), 5.94(2H, s), 6.46-6.55(2H, m), 6.67-6.76(2H, m), 6.77(1H, d, J = 8.9 Hz), 6.85(1H, s), 6.89(1H, d, J = 8.5 Hz), 6.93-6.98(1H, m), 6.97(1H, dd, J = 8.9 Hz, 2.3 Hz), 7.04(1H, d, J = 2.3 Hz), 7.30(1H, d, J = 8.9 Hz), 8.11(1H, dd, J = 8.9 Hz), 2.5 Hz), 8.22(1H, s), 8.25(1H, d, J = 2.5 Hz), 9.45 (1H, s). 1496 3,4-(CH₃)₂Ph— —H —CH₂— —CH2— free ¹H, NMR (CDCl₃) 2.31-2.38(10H, m), 2.57-2.63(2H, m), 2.91-2.97(2H, m), 3.37- 3.40(4H, m), 3.59-3.63(2H, m), 5.93(2H, s), 6.70-6.77(2H, m), 6.84(1H, s), 6.91(1H, d, J = 8.9 Hz), 7.00-7.05(2H, m), 7.17-7.22 (3H, m), 7.60(1H, dd, J = 7.8 Hz, 1.9 Hz), 7.66(1H, d, J = 1.9 Hz), 8.16-8.26(3H, m). 1497

—H —CH₂— —CH₂— free ¹H NMR (DMSO-d₆) 2.41(4H, brs), 2.62 (2H, t, J = 7.5 Hz), 2.81(2H, t, J = 7.5 Hz), 3.32(1H, brs), 3.47(4H, brs), 3.52 (2H, s), 6.00(2H, s), 6.78(1H, d, J = 8.0 Hz), 6.87(1H, d, J = 8.0 Hz), 6.88(1H, d, J = 2.0 Hz), 7.00(2H, d, J = 8.5 Hz), 7.03(1H, d, J = 8.9 Hz), 7.26(2H, d, J = 8.5 Hz), 7.94(1H, s), 8.05(1H, s), 8.10 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.36(1H, d, J = 2.6 Hz), 8.36(1H, d, J = 2.6 Hz), 10.72(1H, s). 1498

—CH₃ —N(CH₃)— —CH₂— hydrochloride mp 145.0-148.0 1499

—CH₃ —N(CH₃)— —CO— free mp 269.0-272.0

TABLE 285

Example No. R₈₆₈ R₈₆₇ R₈₆₈ Form ¹H NMR (solvent) δppm 1500 3,4-Cl₂Ph— —CH₃

hydrochloride (DMSO-d₆) 2.08(3H, s), 3.09(1H, dd, J = 14.2 Hz, 9.7 Hz), 3.40(1H, dd, J = 14.2 Hz, 4.2 Hz), 4.93(1H, dd, J = 9.7 Hz, 4.2 Hz), 7.00(1H, d, J = 8.3 Hz), 7.02(1H, d, J = 8.9 Hz), 7.11(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.20 (1H, d, J = 2.0 Hz), 7.83(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.18 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.23(1H, d, J = 2.0 Hz), 8.44(1H, d, J = 2.5 Hz), 10.57 (1H, s), 12.08(1H, s). 1501 4-CF₃Ph— —CH₃

free (DMSO-d₆) 2.09(3H, s), 3.09(1H, dd, J = 14.1 Hz, 9.6 Hz), 3.40(1H, dd, J = 14.1 Hz, 4.3 Hz), 4.93(1H, dd, J = 9.6 Hz, 4.3 Hz), 6.99(1H, d, J = 8.2 Hz), 7.03(1H, d, J = 8.9 Hz), 7.12(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.20 (1H, d, J = 2.0 Hz), 7.93(2H, d, J = 8.2 Hz), 8.16(2H, d, J = 8.2 Hz), 8.20(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.45(1H, d, J = 2.5 Hz), 10.60(1H, s), 12.07(1H, s). 1502 3-CF₃Ph— —H

free (CDCl₃) 1.28(3H, t, J = 7.0 Hz), 1.46(2H, dq, J = 4.0 Hz, 12.5 Hz), 1.85(2H, brd, J = 12.5 Hz), 1.93(1H, m), 2.73(2H, dt, J = 2.5 Hz, 12.0 Hz), 3.61(2H, brd, J = 12.0 Hz), 4.15(2H, q, J = 7.0 Hz), 6.90(1H, d, J = 9.0 Hz), 6.96(2H, d, J = 9.0 Hz), 7.03(2H, d, J = 9.0 Hz), 7.65(1H, t, J = 8.0 Hz), 7.83(1H, d, J = 8.0 Hz), 7.86(1H, brs), 8.07(1H, d, J = 8.0 Hz), 8.14(1H, brs), 8.18(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.27(1H, d, J = 2.5 Hz).

Example 1503 Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide

To a suspension of 1-(4-piperonylpiperazin-1-yl)-2-{methyl-[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}ethanone (2.65 g, 5.10 mmol) in ethyl acetate (50 mL) was added 5% platinum-carbon (0.20 g) under a nitrogen atmosphere, and the resulting mixture was stirred for 11 hours under a hydrogen atmosphere. The platinum-carbon was separated off by filtration using Celite. To a solution of the resulting filtrate in ethyl acetate was added triethylamine (0.78 mL, 5.61 mmol) under ice cooling, and then to the resulting solution was added 4-(trifluoromethyl)benzoyl chloride (0.80 mL, 5.36 mmol). This reaction solution was stirred for 16 hours, and then added a saturated sodium bicarbonate solution. The resulting solution was stirred at room temperature, and after 20 minutes, extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from acetone-diethyl ether, to thereby yield 3.03 g of the title compound.

Appearance: Pale yellow powder

Melting point: 153.0-154.5° C.; ¹H NMR (CDCl₃) δ 2.12 (3H, s), 2.31-2.52 (4H, m), 3.01 (3H, s), 3.38-3.72 (6H, m), 4.07 (2H, s), 5.95 (2H, s), 6.49-6.61 (2H, m), 6.69-6.78 (2H, m), 6.79-6.88 (2H, m), 6.92 (1H, d, J=8.6 Hz), 7.76 (2H, d, J=8.3 Hz), 7.81-7.90 (1H, m), 7.99 (2H, d, J=8.3 Hz), 8.13 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.23 (1H, d, J=2.6 Hz).

A crude titled product (5.00 g, 7.6 mmol) obtained using the same procedures was recrystallized from ethanol (15 mL), to thereby yield 3.90 g of the title compound.

Appearance: Pale yellow powder

Melting point: 156-158° C.

The following compounds were produced in the same manner as in Example 1503.

Example 1504 N-{6-[2-methyl-4-(2-oxo-3-piperonylimidazolidin-1-yl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide

mp 188.0-189.0° C.

TABLE 286

Example No. R₈₆₉ R₈₇₀ R₈₇₁ R₈₇₂ R₈₇₃ M form mp (°C) or ¹H NMR (solvent) δppm 1505 —Cl —Cl cyclopentyl —H piperonyl 2 oxalate mp 135-139 1506 —Cl —Cl —(CH₂)₂CH₃ —H piperonyl 2 free ¹H NMR (DMSO-(d₆) 0.86(3H, t, J = 7.5 Hz), 1.56(2H, q, J = 7.5 Hz), 2.27 (2H, brs), 2.64(2H, t, J = 7.4 Hz), 2.83(2H, t, J = 7.4 Hz), 3.37-3.48 (6H, m), 3.84(2H, t, J = 7.5 Hz), 5.98 (2H, s), 6.36(1H, d, J = 9.1 Hz), 6.74 (1H, d, J = 7.9 Hz), 6.83(1H, d, J = 7.9 Hz), 6.86(1H, s), 7.16(2H, d, J = 8.2 Hz), 7.30(2H, d, J = 8.2 Hz), 7.70 (1H, dd, J = 9.1 Hz, 2.6 Hz), 7.81(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4 Hz, 1.9 Hz), 8.19(1H, d, J = 1.9 Hz), 8.43(1H, d, J = 2.6 Hz), 10.27(1H, s). 1507 —Cl —Cl —CH₃ —OCH₃ piperonyl 2 free ¹H NMR (CDCl₃) 2.34-2.41(4H, m), 2.62-2.68(2H, m), 2.95- 3.01(2H, m), 3.34(3H, s), 3.38-3.45(4H, m), 3.62-3.65(2H, m), 3.75(3H, s), 5.94 (2H, s), 6.25(1H, d, J = 9.2 Hz), 6.70-6.84(5H, m), 7.12(1H, d, J = 7.6 Hz), 7.53(1H, d, J = 8.2 Hz), 7.67- 7.72(2H, m), 7.97(2H, d, J = 2.0 Hz), 8.24(1H, d, J = 2.5 Hz). 1508 —CF₃ —H —CH₃ —OCH₃ piperonyl 2 free ¹H NMR (CDCl₃) 2.36- 2.37(4H, m), 2.62-2.67(2H, m), 2.94-2.99(2H, m), 3.28-3.45(7H, m), 3.60- 3.64(2H, m), 3.74(3H, s), 5.93(2H, s), 6.25(1H, d, J = 9.1 Hz), 6.70- 6.84(5H, m), 7.11(1H, d, J = 7.6 Hz), 7.67-7.75(3H, m), 7.97(2H, d, J = 7.9 Hz), 8.16-8.32(2H, m). 1509 —Cl —Cl —CH₃ —H benzyl 0 oxalate mp 228-230

TABLE 287

Example No. R₈₇₄ R₈₇₅ R₈₇₆ R₈₇₇ R₈₇₈ Form mp (°C) or ¹H NMR (solvent) δppm 1510 —Cl —Cl —H

piperonyl dioxolate ¹H NMR (DMSO-d₆) 2.36-2.50 (4H, m), 2.73(6H, s), 3.42-3.56 (6H, m), 3.94(2H, s), 4.56(2H, s), 5.98(2H, s), 6.76(1H, d, J = 8.0 Hz), 6.85(1H, d, J = 8.0 Hz), 6.88 (1H, s), 7.13(1H, d, J = 8.9 Hz), 7.23(2H, d, J = 8.8 Hz), 7.45(2H, d, J = 8.8 Hz), 7.83(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4 Hz), 2.0 Hz), 8.20-8.25(2H, m), 8.52(1H, d, J = 2.7 Hz), 10.63(1H, s). 1511 —CF₃ —H —CH₃ —H  piperonyl free ¹H NMR (CDCl₃) 2.11(3H, s), 2.42-2.48(4H, m), 3.45-3.48(4H, m), 3.66-3.70(2H, m), 3.86(2H, s), 4.83(1H, brs), 5.96(2H, s), 6.46-6.52(2H, m), 6.71-6.78(2H, m), 6.83-6.91(3H, m), 7.75-7.82 (3H, m), 7.99(2H, d, J = 8.1 Hz), 8.16(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, d, J = 2.8 Hz). 1512 —Cl —Cl —CH₃ —CH₃  piperonyl hydrochloride mp 183-185 dec 1513 —CF₃ —H —CH₃ —C₂H₅ benzyl maleate mp 165-167 1514 —Cl —Cl —CH₃ —C₂H₃ benzyl free mp 102-105 1515 —CF₃ —H —CH₃ —CH₃  benzyl free mp 110-111 1516 —Cl —Cl —CH₃ —CH₃  benzyl free mp 111-113

TABLE 288

Example No. R₈₇₉ Form mp (°C) or MS 1517   3,4-Cl₂Ph— maleate mp 203-205 1518   3-PhOPh— free MS 686(M⁺ + H) 1519   3,5-Cl₂Ph— free MS 662(M⁺ + H) 1520 3,5-(CH₃)₂Ph— free MS 622(M⁺ + H) 1521 2,3-(CH₃)₂Ph— free MS 622(M⁺ + H) 1522   2,3-Cl₂Ph— free MS 662(M⁺ + H) 1523 1-naphthyl free MS 644(M⁺ + H) 1524 2,4-(CH₃)₂Ph— free MS 622(M⁺ + H) 1525 3,4-(CH₃)₂Ph— free MS 622(M⁺ + H) 1526    3,4-F₂Ph— free MS 630(M⁺ + H) 1527    3-CF₃Ph— free MS 663(M⁺ + H) 1528   3-CF₃OPh— free MS 678(M⁺ + H) 1529   4-CF₃OPh— free MS 678(M⁺ + H) 1530  3-ClPhOCH₂—  free MS 658(M⁺ + H) 1531 2-quinolyl free MS 645(M⁺ + H) 1532 4-quinolyl free MS 645(M⁺ + H) 1533 1-isoquinolyl free MS 645(M⁺ + H) 1534 3-isoquinolyl free MS 645(M⁺ + H) 1535  3,4-Cl₂PhCH₂—  free MS 676(M⁺ + H) 1536  2,4-Cl₂PhCH₂—  free MS 676(M⁺ + H) 1537   3,5-(CF₃)₂Ph—   free MS 731(M⁺ + H) 1538 2,4-Cl₂PhOCH₂—   free MS 691(M⁺ + H) 1539    4-CH₃OPh—   free MS 624(M⁺ + H) 1540  4-CH₃PhCH₂—   free MS 622(M⁺ + H) 1541     PhOCH₂—   free MS 624(M⁺ + H) 1542 3-pyridyl free MS 595(M⁺ + H) 1543 —CH(CH₃)₂    free MS 560(M⁺ + H) 1544 cyclopentyl free MS 586(M⁺ + H) 1545 cyclohexyl free MS 600(M⁺ + H) 1546 cycloheptyl free MS 614(M⁺ + H) 1547 cycloheptylmethyl free MS 628(M⁺ + H) 1548    3-CH₃Ph—   free MS 608(M⁺ + H) 1549  3-(CH₃)₂NPh—  free MS 637(M⁺ + H) 1550  4-(CH₃)₂NPh—  free MS 637(M⁺ + H) 1551  2,5-(CH₃)₂Ph—   free MS 622(M⁺ + H) 1552 —CH(CH₃)Ph free MS 622(M⁺ + H) 1553 —C(CH₃)₃    free MS 574(M⁺ + H)

TABLE 289

Example No. R₈₈₀ MS (M⁺ + H) 1554

626 1555

681 1556

681 1557

663 1558

646 1559

677 1560

661 1561

621 1562

601 1563

660 1564

661 1565

702

TABLE 290

Example No. R₈₈₁ MS (M⁺ + H) 1566

660 1567

679 1568

672 1569

759 1570

680 1571

651 1572

584 1573

616 1574

601 1575

601 1576

662 1577

704 1578

660

TABLE 291

Example No. Xb₂₈ R₈₈₂ R₈₈₃ R₈₈₄ R₈₈₅ R₈₈₆ MS (M⁺ + H) 1579 —NH— —H —H    —H    —H    —H    634 1580 —O— —H —H    —H    —H    —H    634 1581 —O— —H —H    —H    —H    —OCH₃ 664 1582 —NH— —H —H    —OCH₃ —H    —H    663 1583 —NH— —H —H    —Cl    —H    —H    667 1584 —NH— —H —H    —F     —H    —H    651 1585 —N(CH₃)— —H —H    —H    —H    —H    647 1586 —S— —H —H    —H    —H    —H    650 1587 —NH— —H —H    —Br —H    —H    711 1588 —NH— —H —H    —CH₃ —H    —H    648 1589 —NH— —H —H    —OCF₃ —H    —H    717 1590 —NH— —H —OCH₃ —H    —H    —H    664 1591 —NH— —H —Cl   —H    —H    —H    667 1592 —NH— —H —H    —H    —OCH₃ —H    663 1593 —NH— —H —Cl    —H    —Cl    —H    701 1594 —NH— —H —H    —H    —Cl    —H    667 1595 —NH— —H —H    —OCH₃ —OCH₃ —H    693 1596 —O— —CH³ —H    —H    —H    —H    648 1597 —O— —H —H    —OCH₃ —H    —H    664 1598 —O— —H —H    —Cl    —H    —H    668

TABLE 292

Example No. R₈₈₇ R₈₈₈ R₈₈₉ R₈₉₀ R₈₉₁ MS (M⁺ + H) 1599 —H   —OCH₃ —H   —H   —H  650 1600 —H   —H   —OCH₃ —H   —H  650 1601 —H   —Cl    —H   —H   —H  654 1602 —F   —H   —H   —H   —H  638 1603 —H   —F   —H   —H   —H  638 1604 —OCH₃ —OCH₃ —H   —H   —H  680 1605 —OCH₃ —H   —H   —OCH₃ —H  680 1606 —H   —OCH₃ —OCH₃ —H   —H  680 1607 —Cl    —H   —H   —H   —Cl  688 1608 —H   —Cl    —Cl    —H   —H  688 1609 —F   —H   —H   —H   —F  656 1610 —H   —F   —H   —F   —H  656 1611 —H   —OCH₂O—    —H   —H  664 1612 —H   —OCH₃ —OCH₃ —OCH₃ —H  711 1613 —H   —OCH₃ —H   —OCH₃ —H  681 1614 —H   —CF₃   —H   —H   —H  689

Example 1615 Production of 3,4-dichloro-N-[6-(2-fluoro-4-{methyl[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl]amino}phenoxy)pyridin-3-yl]benzenesulfonamide

To a solution of 2-{[4-(5-aminopyridin-2-yloxy)-3-fluorophenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone (15.85 g, 1.9 mmol) in dichloromethane (150 mL) were added 3,4-dichlorobenzenesulfonyl chloride (12.92 g, 1.9 mmol) and pyridine (11 mL, 12.4 mmol), and the resulting solution was stirred for 1 hour at room temperature. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from ethanol, to thereby yield 5.6 g of the title compound.

Appearance: White powder; Melting point: 185.6-187.0° C.;

¹H NMR (CDCl₃) δ 2.45 (4H, t, J=4.6 Hz), 3.01 (3H, s), 3.44 (2H, s), 3.47 (2H, brs), 3.64 (2H, brs), 4.07 (2H, s), 5.95 (2H, s), 6.33-6.44 (2H, m), 6.71-6.78 (2H, m), 6.84-6.87 (2H, m), 6.98 (1H, t, J=9.1 Hz), 7.47 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.51 (2H, dd, J=8.4 Hz, 2.8 Hz), 7.68 (1H, d, J=2.1 Hz), 7.83 (1H, d, J=1.8 Hz); MS 701 (M⁺).

The following compounds were produced in the same manner as in Example 1615.

TABLE 293

Example No. R₈₉₂ R₈₉₃ R₈₉₄ R₈₉₅ M ¹H NMR (solvent) δppm 1616 —CH₃ —H  —H   benzyl 2 (CDCl₃) 2.29-2.37(2H, m), 2.37-2.45(5H, m), 2.61(2H, t, J = 7.9 Hz), 2.95(2H, t, J = 7.9 Hz), 3.35-3.42(2H, m), 3.50(2H, s), 3.59-3.68(2H, m), 6.58(1H, brs), 6.83(1H, d, J = 8.8 Hz), 7.00(2H, d, J = 8.4 Hz), 7.18-7.38(9H, m), 7.55-7.63(3H, m), 7.68(1H, d, J = 2.8 Hz). 1617 —CF₃ —H  —H   benzyl 0 (CDCl₃) 2.46(4H, brs), 3.54(2H, s), 3.54(2H, brs), 3.79 (2H, brs), 6.88(1H, d, J = 8.7 Hz), 7.10(2H, d, J = 8.6 Hz), 7.28-7.33(5H, m), 7.42(2H, d, J = 8.6 Hz), 7.59(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.73(2H, d, J = 8.4 Hz), 7.74(1H, s), 7.86(2H, d, J = 8.4 Hz). 1618 —CF₃ —H  —CH₃  piperonyl 2 (DMSO-d₆) 1.96(3H, s), 2.20-2.40(4H, m), 2.56-2.62 (2H, m), 2.73-2.78(2H, m), 3.32(2H, s), 3.37-3.43(4H, m), 5.99(2H, s), 6.74(1H, dd, J = 7.9 Hz, 1.3 Hz), 6.82-6.93(4H, m), 7.05(1H, dd, J = 8.2 Hz, 1.9Hz), 7.12 (1H, s), 7.52(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.73(1H, d, J = 2.7 Hz), 7.89-7.98(4H, m), 10.45(1H, brs). 1619 —Cl —Cl —OCH₃ piperonyl 2 (DMSO-d₆) 2.20-2.40(4H, m), 2.58-2.64(2H, m), 2.75-2.81(2H, m), 3.37-3.43(6H, m), 3.60(3H, s), 5.97 (2H, s), 6.70-7.00(7H, m), 7.47(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.61(1H, dd, J = 8.5 Hz, 2.1Hz), 7.68(1H, d, J = 2.6 Hz), 7.82-7.86(2H, m), 10.32(1H, brs). 1620 —CF₃ —H  —OCH₃ piperonyl 2 (DMSO-d₆) 2.20-2.40(4H, m), 2.55-2.70(2H, m), 2.75-2.85(2H, m), 3.30-3.50(6H, m), 3.58(3H, s), 5.97 (2H, s), 6.71-7.00(7H, m), 7.47(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.67(1H, d, J = 2.7 Hz), 7.87-7.98(4H, m), 10.40(1H, brs). 1621 —Cl —Cl —CH₃  piperonyl 2 (DMSO-d₆) 1.97(3H, s), 2.20-2.35(4H, m), 2.56-2.62 (2H, m), 2.73-2.79(2H, m), 3.37-3.50(6H, m), 5.98(2H, s), 6.72-6.76(1H, m), 6.82-6.94(4H, m), 7.00-7.13(2H, m), 7.52(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.62(1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.72(1H, d, J = 2.6 Hz), 7.83(1H, d, J = 2.1 Hz), 7.85(1H, d, J = 8.5 Hz), 10.36(1H, brs). 1622 —CF₃ —H  —F   piperonyl 2 (DMSO-d₆) 2.20-2.35(4H, m), 2.60-2.66(2H, m), 2.78-2.84(2H, m), 3.39(2H, s), 3.42-3.50(4H, m), 5.99(2H, s), 6.72-6.76(1H, m), 6.83-6.86(2H, m), 7.03-7.24(4H, m), 7.55(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.75(1H, d, J = 2.7 Hz), 7.90-7.99(4H, m), 10.52(1H, brs).

TABLE 294

Example No. R₈₉₆ R₈₉₇ R₈₉₈ mp (°C) or ¹H NMR (solvent) δppm 1623 —CF₃ —H 

mp 208.0-209.0 1624 —Cl —Cl

¹H NMR (CDCl₃) 1.70(1H, brs), 2.42(4H, t, J = 5.1 Hz), 3.39(4H, t, J = 5.1 Hz), 3.43(2H, s), 4.38(2H, d, J = 5.4 Hz), 4.80 (1H, t, J = 5.4 Hz), 5.94(2H, s), 6.73(2H, s), 6.84(1H, s), 6.86(1H, d, J = 8.5 Hz), 7.00(2H, d, J = 8.6 Hz), 7.27(2H, d, J = 8.6 Hz), 7.51(2H, d, J = 2.5 Hz), 7.58(1H, dd, J = 8.7 Hz, 2.7 Hz), 7.73(1H, dd, J = 2.7 Hz, 0.7 Hz), 7.83(1H, t, J = 2.5 Hz). 1625 —Cl —Cl

¹H NMR (DMSO-d₆) 2.20-2.35(4H, m), 2.56-2.62(2H, m), 2.77-2.82(2H, m), 3.30-3.50(6H, m). 5.98(2H, s), 6.70-6.80 (1H, m), 6.82-6.90(3H, m), 6.93-6.97(2H, m), 7.05-7.10(1H, m), 7.24-7.35(1H, m), 7.54(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.64(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.80(1H, d, J = 2.8 Hz), 7.86(1H, d, J = 8.4 Hz), 7.89(1H, d, J = 2.0 Hz), 10.43(1H, brs). 1626 —CF₃ —H 

¹H NMR (DMSO-d₆) 2.20-2.30(4H, m), 2.55-2.61(2H, m), 2.76-2.82(2H, m), 3.30-3.40(6H, m), 5.98(2H, s), 6.70-6.80 (1H, m), 6.82-6.95(5H, m), 7.05(1H, d, J = 7.7 Hz), 7.23-7.30(1H, m), 7.54(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.80(1H, d, J = 2.8 Hz), 7.90-7.99(4H, m), 10.52(1H, brs). 1627 —Cl —Cl

¹H NMR (DMSO-d₆) 2.25-2.45(4H, m), 3.42(2H, s), 3.50-3.75(4H, m), 5.99(2H, s), 6.75-6.80(1H, m), 6.83-6.88(2H, m), 7.00(1H, d, J = 8.8 Hz), 7.05-7.10(1H, m), 7.25-7.29(1H, m), 7.35-7.65(6H, m), 7.8 0(1H, d, J = 2.7 Hz), 7.86(1H, d, J = 8.4 Hz), 7.90(1H, d, J = 2.1 Hz), 10.44 (1H, brs).

TABLE 295

Example No. R₈₉₉ R₉₀₀ M mp (°C) or ¹H NMR (DMSO-d₆) δppm 1628  4-CF₃Ph— piperonyl 2 ¹H NMR 1.89-2.06(5H, m), 3.17-3.31(2H, m), 3.52-3.71(2H, m), 4.39(2H, s), 5.98(2H, m), 6.75(1H, dd, J = 1.2 Hz, 7.9 Hz), 6.83(1H, d, J = 1.2 Hz), 6.86(1H, d, J = 7.9 Hz), 6.92(1H, d, J = 8.6 Hz), 6.95(1H, d, J = 8.8 Hz), 7.09(1H, dd, J = 2.5 Hz, 8.6 Hz), 7.18(1H, d, J = 2.5 Hz), 7.53(1H, dd, J = 2.8 Hz, 8.8 Hz), 7.75(1H, d, J = 2.8 Hz), 7.90(2H, d, J = 8.4 Hz), 7.96(2H, d, J = 8.4 Hz), 10.47(1H, s). 1629 3,4-Cl₂Ph— piperonyl 2 ¹H NMR 1.89-2.09(5H, m), 3.19-3.33(2H, m), 3.50-3.71(2H, m), 4.39(2H, s), 5.98(2H, s), 6.73-6.78(1H, m), 6.83(1H, d, J = 1.3 Hz), 6.86(1H, d, J = 7.9 Hz), 6.93(1H, d, J = 8.6 Hz), 6.97(1H, d, J = 8.8 Hz), 7.10(1H, d, J = 2.4 Hz, 8.6 Hz), 7.19(1H, d, J = 2.4 Hz), 7.53(1H, dd, J = 2.7 Hz, 8.8 Hz), 7.62(1H, dd, J = 2.1 Hz, 8.4 Hz), 7.75(1H, d, J = 2.7 Hz), 7.83(1H, d, J = 2.1 Hz), 7.85(1H, d, J = 8.4 Hz), 10.37(1H, s). 1630   4-CF₃Ph— piperonyl 1 mp 163.0-164.0 1631 3,4-Cl₂Ph— piperonyl 1 mp 190.5-191.0 1632   4-CF₃Ph— 3,4-(CH₃O)₂PhCH₂— 2 mp 141.0-143.0 1633 3,4-Cl₂Ph— 3,4-(CH₃O)₂PhCH₂— 2 mp 135.0-136.0 1634 3,4-Cl₂Ph—

2 mp 181.0-183.0

TABLE 296

Example No. R₉₀₁ R₉₀₂ M ¹H NMR (CDCl₃) δppm 1635 3,4-Cl₂Ph— —CH₃  0 1.27(3H, t, J = 7.1 Hz), 1.84-2.05(4H, m), 2.06(3H, s), 2.40-2.48(1H, m), 2.71-2.81(2H, m), 3.56-3.61(2H, m 4.16(2H, q, J = 7.1 Hz), 6.74-6.79(3H, m), 6.89(1H, d, J = 8.6 Hz), 7.47-7.57(4H, m) 7.76-7.79(2H, m). 1636 4-CF₃Ph— —CH₃  0 1.27(3H, t, J = 7.1 Hz), 1.84-2.00(4H, m), 2.03(3H, s), 2.42-2.51(1H, m), 2.70-2.79(2H, m), 3.55-3.60(2H, m), 4.16(2H, q, J = 7.1 Hz), 6.68-6.78(3H, m), 6.87(1H, d, J = 8.6 Hz), 7.55 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.67(2H, d, J = 8.2 Hz), 7.79-7.84(3H, m), 8.10(1H, s). 1637 3,4-Cl₂Ph— —H   1 1.27(3H, t, J = 7.1 Hz), 1.39-1.48(2H, m), 1.81-1.92(3H, m), 2.29(2H, d, J = 6.9 Hz), 2.71(2H, dd, J = 12.2 Hz, 9.9 Hz), 3.59(2H, d, J = 12.4 Hz), 4.15(2H, q, J = 7.3 Hz), 6.78(1H, d, J = 8.7 Hz), 6.90-6.98(4H, m), 7.50(2H, d, J = 1.2 Hz), 7.55(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.78-7.81(3H, m). 1638 4-CF₃Ph— —H   1 1.27(3H, J = 7.1 Hz), 1.36-1.48(2H, m), 1.81-1.92(3H, m), 2.29(2H, d, J = 6.9 Hz), 2.70(2H, dd, J = 12.2 Hz, 9.9 Hz), 3.59(2H, d, J = 12.2 Hz), 4.15(2H, q, J = 7.3 Hz), 6.75(1H, d, J = 8.9 Hz), 6.89-6.97(4H, m), 7.55(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.68(2H, d, J = 8.7 Hz), 7.79-7.85(4H, m). 1639 4-CF₃Ph— —OCH₃ 1 1.27(3H, t, J = 7.1 Hz), 1.30-1.48(2H, m), 1.82-2.05(3H, m), 2.29(2H, d, J = 6.9 Hz), 2.69-2.77(2H, m), 3.60(2H, d, J = 12.2 Hz), 3.68(3H, s), 4.15(2H, q, J = 7.1 Hz), 6.48(1H, dd, J = 8.6 Hz, 2.5 Hz), 6.56(1H, d, J = 2.6 Hz), 6.76(1H, d, J = 8.7 Hz), 6.94(1H, d, J = 8.7 Hz), 7.54(1H, dd, J = 8.7 Hz, 2.8 z), 7.66-7.73(4H, m), 7.83(2H, d, J = 8.2 Hz). 1640 3,4-Cl₂Ph— —OCH₃ 1 1.28(3H, t, J = 7.1 Hz), 1.30-1.48(2H, m), 1.82-2.05(3H, m), 2.29(2H, d, J = 6.9 Hz), 2.73(2H, t, J = 12.0 Hz), 3.60(2H, d, J = 12.2 Hz), 3.69(3H, s), 4.16(2H, q, J = 7.1 Hz), 5.29(2H s), 6.48(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.56(1H, d, J = 2.6 Hz), 6.77(1H, d, J = 8.7 Hz), 6.94(1H, d, J = 8.6 Hz), 7.46-7.75(3H, m), 7.79-7.80(3H, m). 1641 4-CF₃Ph— —H   0 1.27(3H, t, J = 7.1 Hz , 1.81-1.94(2H, m), 2.00-2.05(2H, m), 2.40-2.54(1H, m), 2.71-2.82(2H, m), 3.56-3.60(2H, m), 4.16(2H, q, J = 7.1 Hz), 6.78(1H, d, J = 8.9 Hz), 6.90- 6.99(5H, m), 7.56(1H, dd, J = 8.9 Hz, 2.8 z), 7.70(2H, d, J = 8.4 Hz), 7.77(1H, d, J = 2.8 Hz), 7.84(2H, d, J = 8.2 Hz). 1642 3,4-Cl₂Ph— —H   0 1.27(3H, t, J = 7.3 Hz), 1.89-1.94(2H, m), 2.01-2.05(2H, m), 2.38-2.54(1H, m), 2.72-2.82(2H, m), 3.56-3.61(2H, m), 4.16(2H, q, J = 7.1 Hz), 6.80(1H, d, J = 8.7 Hz), 6.91- 7.00(4H, m), 7.26(1H, brs), 7.51-7.58(3H, m), 7.77(1H, d, J = 2.8 Hz), 7.82(1H, s).

TABLE 297

Example No. R₉₀₃ R₉₀₄ M ¹H NMR (CDCl₃) δppm 1643 4-CF₃Ph— —CH₃ 1 1.27(3H, t, J = 7.1 Hz), 1.38-1.43(2H, m), 1.80- 2.01(3H, m), 2.02(3H, s), 2.29(2H, d, J = 6.9 Hz), 2.69(2H, t, J = 12.0 Hz), 3.58(2H, d, J = 12.0 Hz), 4.15(2H, q, J = 7.3 Hz), 6.67-6.87(4H, m), 7.53- 7.68(3H, m), 7.79-7.84(4H, m). 1644 3,4-Cl₂Ph— —CH₃ 1 1.27(3H, t, J = 7.1 Hz), 1.30-1.48(2H, m), 1.80- 2.04(3H, m), 2.05(3H, s), 2.29(2H, d, J = 6.9 Hz), 2.69(2H, t, J = 12.0 Hz), 3.58(2H, d, J = 12.0 Hz), 4.15(2H, q, J = 7.1 Hz), 6.71-6.79(3H, m), 6.88(1H, d, J = 8.6 Hz), 7.49-7.57(4H, m), 7.77(2H, d, J = 2.8 Hz).

TABLE 298

Example No. R₉₀₅ R₉₀₆ R₉₀₇ Form mp (° C.) 1645 4-CF₃Ph— —H —CH₃ hydrochloride 189.0-191.0 1646 3,4-Cl₂Ph— —H —CH₃ free 180.0-182.0 1647 4-CF₃Ph— —CH₃ —H free 129.5-131.0 1648 3,4-Cl₂Ph— —CH₃ —H free 129.0-130.0

TABLE 299

Example No. R₉₀₈ R₉₀₉ ¹H NMR (DMSO-d₆) δppm 1649

—F 2.20-2.35(4H, m), 2.60-2.66(2H, m), 2.77-2.83(2H, m), 3.39(2H, s), 3.39-3.50(4H, m), 5.99(2H, s), 6.65-6.76(1H, m), 6.83-6.86(2H, m), 7.01-7.25(4H, m), 7.30-7.40(1H, m), 7.55(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.72(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.78(1H, d, J = 2.3 Hz), 8.00-8.05(1H, m), 10.65(1H, brs). 1650

—CH₃ 1.94(3H, s), 2.20-2.35(4H, m), 2.56-2.61(2H, m), 2.72- 2.78(2H, m), 3.38(2H, s), 3.38-3.50(4H, m), 5.98(2H, s), 6.72-6.75(1H, m), 6.82-6.91(4H, m), 7.03-7.12(2H, m), 7.30-7.45(1H, m), 7.52(1H, dd, J = 8.8 Hz, 2.2 Hz), 7.71(1H, dd, J = 8.7 Hz, 2.1 Hz), 7.78(1H, d, J = 2.7 Hz), 7.98-8.04(1H, m), 10.58(1H, brs). 1651 3,4-Cl₂Ph— —H 2.20-2.35(4H, m), 2.57-2.63(2H, m), 2.76-2.82(2H, m), 3.39(2H, s), 3.39-3.43(4H, m), 5.99(2H, s), 6.70-6.76(1H, m), 6.82-6.86(2H, m), 6.93-6.98(3H, m), 7.22-7.26(2H, m), 7.51-7.55(1H, m), 7.63(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.79(1H, d, J = 2.7 Hz), 7.86(1H, d, J = 8.5 Hz), 7.88(1H, d, J = 2.1 Hz), 10.41(1H, brs). 1652 4-CF₃Ph— —H 2.20-2.35(4H, m), 2.57-2.63(2H, m), 2.76-2.82(2H, m), 3.32(2H, s), 3.32-3.50(4H, m), 5.98(2H, s), 6.70-6.76(1H, m), 6.82-6.86(2H, m), 6.92-6.98(3H, m), 7.22-7.25(2H, m), 7.52(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.78(1H, d, J = 2.7 Hz), 7.90-7.99(4H, m), 10.50(1H, brs). 1653 3,4-Cl₂Ph— —F 2.20-2.35(4H, m), 2.60-2.66(2H, m), 2.78-2.84(2H, m), 3.39(2H, s), 3.42-3.50(4H, m), 5.99(2H, s), 6.70-6.76(1H, m), 6.82-6.86(2H, m), 7.04-7.30(4H, m), 7.55(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.63(1H, dd, J = 8.5 Hz, 2.2 Hz), 7.75(1H, d, J = 2.6 Hz), 7.85(1H, d, J = 8.5 Hz), 7.88(1H, d, J = 2.1 Hz), 10.43(1H, brs).

TABLE 300

Example No. R₉₁₀ R₉₁₁ R₉₁₂ R₉₁₃ mp (° C.) or ¹H NMR (solvent) δppm 1654 4-CF₃Ph— —F —H —CH₃ mp 186.0-188.0 1655 3,4-Cl₂Ph— —F —H —C₂H₅ mp 157.3-160.1 1656 4-CF₃Ph— —F —H —C₂H₅ mp 173.0-176.8 1657 4-CF₃Ph— —OCH₃ —H —C₂H₅ mp 179.0-181.0 1658 3,4-Cl₂Ph— —OCH₃ —H —C₂H₅ mp 175.0-176.0 1659 4-CF₃Ph— —CH₃ —H —CH₃ mp 170.0-172.0 1660 3,4-Cl₂Ph— —CH₃ —H —CH₃ mp 170.0-173.0 1661 3,4-Cl₂Ph— —H —H —CH₃ mp 135.0-137.0 1662 4-CF₃Ph— —H —H —CH₃ mp 189.0-190.0 1663 4-CF₃Ph— —F —F —CH₃ mp 159.5-160.0 1664 3,4-Cl₂Ph— —F —F —CH₃ mp 136.0-137.0 1665 Ph— —H —H —CH₃ ¹H NMR (CDCl₃) 2.41-2.45(4H, m), 3.01(3H, s), 3.43 (2H, s), 3.47-3.49(2H, m), 3.63(2H, brs), 4.07(2H, s), 5.95(2H, s), 6.63(1H, brs), 6.66(2H, d, J = 9.1 Hz), 6.71-6.77(3H, m), 6.85(1H, brs), 6.93(2H, d, J = 9.1 Hz), 7.42- 7.59(4H, m), 7.68-7.73(3H, m). 1666 —(CH₂)₃CH₃ —H —H —CH₃ ¹H NMR (CDCl₃) 0.93(3H, t, J = 7.3 Hz), 1.36-1.50(2H, m), 1.75-1.87(2H, m), 2.41- 2.45(4H, m), 3.01-3.06(5H, m), 3.44(2H, s), 3.47-3.49(2H, m), 3.63(2H, brs), 4.09(2H, s), 5.95(2H, s), 6.37(1H, brs), 6.69(2H, d, J = 9.1 Hz), 6.72-6.77(2H, m), 6.82-6.96(2H, m), 6.99(2H, d, J = 9.1 Hz), 7.65(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.00(1H, d, J = 2.8 Hz). 1667 4-CH₃Ph— —H —H —CH₃ ¹H NMR (CDCl₃) 2.39(3H, s), 2.41-2.44(4H, m), 3.01(3H, s), 3.43(2H, s), 3.47-3.49(2H, m), 3.62(2H, brs), 4.07(2H, s), 5.95(2H, s), 6.46-6.51(1H, m), 6.66(2H, d, J = 8.9 Hz), 6.70-6.77(3H, m), 6.85(1H, brs), 6.94(2H, d, J = 8.9 Hz), 7.23(2H, d, J = 8.1 Hz), 7.50(1H, dd, J = 8.2 Hz, 2.8 Hz), 7.58(2H, d, J = 8.4 Hz), 7.66(1H, d, J = 2.6 Hz). 1668

—F —H —CH₃ ¹H NMR (DMSO-d₆) 2.25-2.45(4H, m), 2.91(3H, s), 3.42 (6H, brs), 4.26(2H, s), 5.99(2H, s), 6.30-6.40(1H, m), 6.45-6.55(1H, m), 6.74-6.77(1H, m), 6.83-7.05(4H, m), 7.30-7.45(1H, m), 7.51(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.71 (1H, dd, J = 8.7 Hz, 2.5 Hz), 7.79(1H, d, J = 2.7 Hz), 8.02(1H, dd, J = 8.9 Hz, 5.9 Hz), 10.60(1H, brs). 1669 3,4-Cl₂Ph— —COOCH₃ —H —C₂H₅ ¹H NMR (DMSO-d₆) 1.11(3H, t, J = 7.0 Hz), 2.20-2.5 (4H, m), 3.30-3.50(11H, m), 4.22(2H, s), 5.99(2H, s), 6.75-7.00(7H, m), 7.45-7.55(1H, m), 7.60-7.70 (2H, m), 7.83- 7.87(2H, m), 10.31(1H, brs).

TABLE 301

Example No. R₉₁₄ R₉₁₅ R₉₁₆ R₉₁₇ ¹H NMR (solvent) δppm 1670

—F —CH₃ —H (DMSO-d₆) 2.23(3H, s), 2.25-2.45(4H, m), 2.91(3H, s), 3.41(6H, brs), 3.83(3H, s), 4.25(2H, s), 5.99(2H, s), 6.30-6.40(1H, m), 6.45-6.55(1H, m), 6.75-6.77(1H, m), 6.83- 6.99(4H, m), 7.07(1H, d, J = 8.5 Hz), 7.30- 7.40(1H, m), 7.48(1H, d, J = 1.9 Hz), 7.51(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.74(1H, d, J = 2.6 Hz), 9.85(1H, brs). 1671 3,4-Cl₂Ph— —CH₃ —CH₃ —CH₃ (CDCl₃) 1.28(3H, d, J = 6.6 Hz), 2.05(3H, s), 2.08-2.21 (1H, m), 2.33(2H, brs), 2.50(1H, brs), 2.75(3H, s), 3.29-3.57(3H, m), 3.38(2H, s), 3.77(1H, brs), 4.55(1H, q, J = 6.6 Hz), 5.94(2H, s), 6.56-6.59(2H, m), 6.68-6.75(2H, m), 6.79-6.82(2H, m), 6.89- 6.93(1H, m), 7.51-7.52(2H, m), 7.57(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.71(1H, dd, J = 2.8 Hz, 0.5 Hz), 7.79(1H, dd, J = 1.7 Hz, 0.8 Hz). 1672 4-CF₃Ph— —CH₃ —CH₃ —CH₃ (CDCl₃) 1.28(3H, d, J = 6.4 Hz), 2.07(3H, s), 2.17-2.20 (1H, m), 2.33-2.36(2H, m), 2.47-2.49(1H, m), 2.75(3H, s), 3.28- 3.30(1H, m), 3.38(2H, s), 3.38-3.50(1H, m), 3.52-3.56(1H, m), 3.77-3.82(1H, m), 4.55(1H, q, J = 6.6 Hz), 5.94(2H, s), 6.55- 6.59(2H, m), 6.68-6.75(2H, m), 6.78- 6.82(2H, m), 6.89-6.92(1H, m), 7.57(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.70(1H, dd, J = 2.8 Hz, 0.5 Hz), 7.73(2H, d, J = 8.3 Hz), 7.85(2H, d, J = 8.3 Hz). 1673

—F —CH₃ —H (DMSO-d₆) 2.20-2.50(4H, m), 2.91(3H, s), 3.35-3.50 (6H, m), 4.26(2H, s), 5.99(2H, s), 6.20-6.30(1H, m), 6.45-6.55(1H, m), 6.75- 6.80(1H, m), 6.84-7.01(4H, m), 7.52(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.79(1H, d, J = 2.8 Hz), 7.97(1H, dd, J = 8.2 Hz, 1.5 Hz), 8.09(1H, d, J = 8.2 Hz), 8.29(1H, d, J = 1.5 Hz), 10.80(1H, brs). 1674 4-PhOPh— —F —CH₃ —H (DMSO-d₆) 2.20-2.45(4H, m), 2.92(3H, s), 3.35-3.50 (6H, m), 4.26(2H, s), 5.99(2H, s), 6.35-6.45(1H, m), 6.45-6.60(1H, m), 6.76(1H, d, J = 7.9 Hz), 6.83-6.87 (2H, m), 6.93-7.14(6H, m), 7.20-7.30(1H, m), 7.43- 7.55(3H, m), 7.68-7.74(3H, m), 10.17(1H, brs). 1675 3,4-Cl₂Ph— —CF₃ —C₂H₅ —H (DMSO-d₆) 1.11(3H, t, J = 6.9 Hz), 2.25- 2.45(4H, m), 3.35-3.55(8H, m), 4.27(2H, s), 5.99(2H, s), 6.67-6.88(5H, m), 6.94- 7.05(2H, m), 7.52(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.63(1H, dd, J = 8.4 Hz, 2.2 Hz), 7.75(1H, d, J = 2.7 Hz), 7.83-7.87(2H, m), 10.38(1H, brs).

TABLE 302

Example No. R₉₁₈ R₉₁₉ R₉₂₀ R₉₂₁ R₉₂₂ Form Property 1676 4-CF₃Ph— —F —F —H —CH₃ free mp 199.0-200.0° C. 1677 3,4-Cl₂Ph— —F —F —H —CH₃ free mp 198.0-199.0° C. 1678 4-CF₃Ph— —F —H —F —CH₃ free mp 176.0-177.0° C. 1679 3,4-Cl₂Ph— —F —H —F —CH₃ free mp 115.0-116.0° C. 1680 4-CF₃Ph— —F —H —F —C₂H₅ free mp 173.0-174.0° C. 1681 3,4-Cl₂Ph— —F —H —F —C₂H₅ free mp 156.0-157.0° C. 1682 3,4-Cl₂Ph— —CH₃ —H —CH₃ —C₂H₅ hydro- ¹H NMR (DMSO-d₆) δ 0.95(3H, t, chloride J = 7.0 Hz), 1.97(3H, s), 2.28(3H, s), 2.70-4.40(14H, m), 6.07(2H, s), 6.86(1H, brs), 6.93-7.10(3H, m), 7.20-7.40(2H, m), 7.56(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.66 (1H, dd, J = 8.5 Hz, 2.1 Hz), 7.78(1H, d, J = 2.6 Hz), 7.85-7.88(2H, m), 10.55(1H, brs), 11.47(1H, brs). 1683 4-CF₃Ph— —CH₃ —H —CH₃ —C₂H₅ free ¹H NMR (DMSO-d₆) δ 0.92(3H, t, J = 7.0 Hz), 1.91(3H, s), 2.16(3H, s), 2.20-2.40(4H, m), 2.98(2H, q, J = 7.0 Hz), 3.30-3.50(6H, m), 3.77(2H, s), 5.98(2H, s), 6.72- 6.76(2H, m), 6.82-6.90(3H, m), 7.01(1H, s), 7.51(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.75(1H, d, J = 2.7 Hz), 7.89-7.99(4H, m), 10.45(1H, brs). 1684 3,4-Cl₂Ph— —F —H —H —H hydro- ¹H NMR (DMSO-d₆) δ 2.75- chloride 3.65(7H, m), 3.85-4.55(6H, m), 6.08(2H, s), 6.47-6.50(1H, m), 6.59(1H, dd, J = 13.5 Hz, 2.6 Hz), 6.92-7.01(4H, m), 7.20(1H, s), 7.52(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.64(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.76(1H, d, J = 2.5 Hz), 7.86(1H, d, J = 8.6 Hz), 7.89(1H, d, J = 2.2 Hz), 10.45(1H, s), 10.90 (1H, brs). 1685 4- —H —H —H —CH₃ free MS 646(M⁺ + H) CH₃OPh— 1686 1-naphthyl —H —H —H —CH₃ free MS 666(M⁺ + H) 1687 2-naphthyl —H —H —H —CH₃ free MS 666(M⁺ + H) 1688 2-CH₃Ph— —H —H —H —CH₃ free MS 630(M⁺ + H) 1689 4-FPh— —H —H —H —CH₃ free MS 634(M⁺ + H) 1690 2-CF₃Ph— —H —H —H —CH₃ free MS 684(M⁺ + H) 1691 2-ClPh— —H —H —H —CH₃ free MS 650(M⁺ + H)

TABLE 303

Example No. R₉₂₃ R₉₂₄ MS (M⁺ + H) 1692 2-thienyl —H 622 1693 2-CF₃OPh— —H 700 1694 3-CF₃OPh— —H 700 1695 3-CH₃OPh— —H 646 1696 3-FPh— —H 634 1697 2,3-Cl₂Ph— —H 684 1698 3-CF₃Ph— —H 684 1699 4-CF₃OPh— —H 700 1700 4-bipenylyl —H 692 1701 3,4-(CH₃O)₂Ph— —H 676 1702 2,5-(CH₃O)₂Ph— —H 676 1703 3-CH₃Ph— —H 630 1704 2,5-Cl₂Ph— —H 684 1705 3-ClPh— —H 650 1706 2,4-Cl₂Ph— —H 684 1707 2,3,4-Cl₂Ph— —H 720 1708 —C₂H₅ —H 568 1709 2,6-Cl₂Ph— —H 684 1710 4-CH₃OPh— —F 664 1711 4-ClPh— —F 668 1712 1-naphthyl —F 684 1713 2-naphthyl —F 684 1714 2-CH₃Ph— —F 648 1715 4-FPh— —F 652 1716 2-CF₃Ph— —F 702 1717 2-thienyl —F 640 1718 2-ClPh— —F 668 1719 2-CF₃OPh— —F 718 1720 3-CF₃OPh— —F 718 1721 2-CNPh— —F 660 1722 3-CH₃OPh— —F 664 1723 3-FPh— —F 652 1724 2,3-Cl₂Ph— —F 702 1725 3-CF₃Ph— —F 702 1726 4-CF₃OPh— —F 718 1727 4-biphenylyl —F 710 1728 3,4-(CH₃O)₂Ph— —F 694 1729 2,5-(CH₃O)₂Ph— —F 694

TABLE 304

Example No. R₉₂₅ R₉₂₆ MS (M⁺ + H) 1730 3-CH₃Ph— —F 648 1731 2,5-Cl₂Ph— —F 702 1732 3-ClPh— —F 668 1733 2,4-Cl₂Ph— —F 702 1734 —CH₃ —F 572 1735 2,3,4-Cl₃Ph— —F 738 1736 —(CH₂)₃CH₃ —F 614 1737 —C₂H₅ —F 586 1738 2,6-Cl₂Ph— —F 702 1739 4-CH₃OPh— —CH₃ 660 1740 4-ClPh— —CH₃ 664 1741 1-naphthyl —CH₃ 680 1742 2-naphhyl —CH₃ 680 1743 2-CH₃Ph— —CH₃ 644 1744 4-FPh— —CH₃ 648 1745 2-CF₃Ph— —CH₃ 698 1746 2-thienyl —CH₃ 636 1747 2-ClPh— —CH₃ 664 1748 2-CF₃OPh— —CH₃ 714 1749 2-CNPh— —CH₃ 656 1750 3-CH₃OPh— —CH₃ 660 1751 3-FPh— —CH₃ 648 1752 2,3-Cl₂Ph— —CH₃ 698 1753 3-CF₃Ph— —CH₃ 698 1754 4-CF₃OPh— —CH₃ 714 1755 4-biphenylyl —CH₃ 706 1756 3,4-(CH₃O)₂Ph— —CH₃ 690 1757 2,5-(CH₃O)₂Ph— —CH₃ 690 1758 3-CH₃Ph— —CH₃ 644 1759 2,5-Cl₂Ph— —CH₃ 698 1760 3-ClPh— —CH₃ 664 1761 2,4-Cl₂Ph— —CH₃ 698 1762 —CH₃ —CH₃ 568 1763 2,3,4-Cl₃Ph— —CH₃ 734 1764 —(CH₂)₃CH₃ —CH₃ 610 1765 —C₂H₅ —CH₃ 582 1766 2,6-Cl₂Ph— —CH₃ 698 1767 2,4,5-Cl₃Ph— —H 719

TABLE 305

Example No. R₉₂₇ R₉₂₈ MS (M⁺ + H) 1768 2,4,6-(CH₃)₃Ph— —H 658 1769 4-C₂H₅Ph— —H 644 1770 2,5-(CH₃)₂Ph— —H 644 1771 2-FPh— —H 634 1772 2,4,6-(CH₃)₃Ph— —F 676 1773 4-CH₃Ph— —F 648 1774 4-C₂H₅Ph— —F 662 1775 2,5-(CH₃)₂Ph— —F 662 1776 2-FPh— —F 652 1777 2,4,5-Cl₃Ph— —CH₃ 732 1778 2,4,6-(CH₃)₃Ph— —CH₃ 672 1779 4-CH₃Ph— —CH₃ 644 1780 4-C₂H₅Ph— —CH₃ 658 1781 2,5-(CH₃)₂Ph— —CH₃ 658 1782 2-FPh— —CH₃ 648 1783 4-BrPh— —H 696 1784 —CH(CH₃)₃ —H 582 1785 8-quinolyl —H 667 1786 3-CNPh— —H 641 1787 4-PhOPh— —H 708 1788 3-BrPh— —H 696 1789 4-CNPh— —H 641 1790 2,4-F₂Ph— —H 652 1791 4-BrPh— —F 714 1792 —CH(CH₃)₂ —F 600 1793 8-quinolyl —F 685 1794 3-CNPh— —F 659 1795 4-CNPh— —F 659 1796 2,4-F₂Ph— —F 670 1797 4-BrPh— —CH₃ 710 1798 —CH(CH₃)₂ —CH₃ 596 1799 8-quinolyl —CH₃ 681 1800 3-CNPh— —CH₃ 655 1801 3-BrPh— —CH₃ 710 1802 4-CNPh— —CH₃ 655 1803 2,4-F₂Ph— —CH₃ 666 1804 2,4,6-Cl₃Ph— —H 720 1805 2,4,6-Cl₃Ph— —F 738

TABLE 306

Example No. R₉₂₉ R₉₃₀ MS (M⁺ + H) 1806 2,4,5-Cl₃Ph— —F 738 1807 2,4,6-Cl₃Ph— —CH₃ 734 1808 Ph— —F 634 1809 Ph— —CH₃ 630 1810 2,5-F₂Ph— —F 670 1811 2,5-F₂Ph— —CH₃ 666 1812 2,6-F₂Ph— —CH₃ 666 1813 3,4-F₂Ph— —CH₃ 666 1814 2,6-F₂Ph— —H 652 1815 3,4-F₂Ph— —H 652 1816 2,6-F₂Ph— —F 670 1817 3,4-F₂Ph— —F 670 1818 —CH₃ —H 554 1819

—H 680 1820

—H 660 1821

—F 698 1822

—CH₃ 694 1823

—CH₃ 674 1824

—H 718 1825

—H 668 1826

—H 698 1827

—H 718

TABLE 307

Example No. R₉₃₁ R₉₃₂ MS (M⁺ + H) 1828

—H 675 1829

—H 686 1830

—H 742 1831

—H 672 1832

—H 660 1833

—H 688 1834

—F 716 1835

—F 736 1836

—F 718 1837

—F 678 1838

—F 747 1839

—F 706 1840

—CH₃ 712

TABLE 308

Example No. R₉₃₃ R₉₃₄ MS (M⁺ + H) 1841

—CH₃ 732 1842

—CH₃ 689 1843

—CH₃ 700 1844

—CH₃ 714 1845

—CH₃ 674 1846

—CH₃ 743 1847

—CH₃ 702 1848

—H 700 1849

—H 709 1850

—H 680 1851

—H 674 1852

—H 698

TABLE 309

Example No. R₉₃₅ R₉₃₆ MS (M⁺ + H) 1853

—H 682 1854

—H 710 1855

—H 707 1856

—F 727 1857

—F 698 1858

—F 692 1859

—F 716 1860

—F 700 1861

—F 728 1862

—F 725 1863

—CH₃ 723

TABLE 310

Example No. R₉₃₇ R₉₃₈ MS (M⁺ + H) 1864

—CH₃ 694 1865

—CH₃ 688 1866

—CH₃ 712 1867

—CH₃ 696 1868

—CH₃ 724 1869

—CH₃ 721 1870

—H 730 1871

—F 736 1872

—F 704 1873

—CH₃ 732 1874

—CH₃ 682 1875

—H 668

TABLE 311

Example No. R₉₃₉ R₉₄₀ MS (M⁺ + H) 1876

—H 660 1877

—H 664 1878

—H 648 1879

—H 664 1880

—H 714 1881

—H 664 1882

—F 678 1883

—F 682 1884

—F 666 1885

—F 682 1886

—F 686 1887

—CH₃ 682 1888

—F 682

TABLE 312

Example No. R₉₄₁ R₉₄₂ MS (M⁺ + H) 1889

—CH₃ 674 1890

—CH₃ 678 1891

—CH₃ 662 1892

—CH₃ 678 1893

—CH₃ 728 1894

—CH₃ 678 1895

—F 732 1896

—F 760 1897

—CH₃ 756 1898 3-BrPh— —F 714 1899 4-PhOPh— —CH₃ 722 1900

—F 690 1901

—CH₃ 686

TABLE 313

Example No. R₉₄₃ R₉₄₄ MS (M⁺ + H) 1902

—H 678 1903

—H 658 1904

—H 700 1905

—H 700 1906

—H 674 1907

—H 620 1908

—F 696 1909

—F 676 1910

—F 718 1911

—F 718 1912

—F 692 1913

—F 638

TABLE 314

Example No. R₉₄₅ R₉₄₆ MS (M⁺ + H) 1914

—CH₃ 692 1915

—CH₃ 672 1916

—CH₃ 714 1917

—CH₃ 714 1918

—CH₃ 688 1919

—CH₃ 634 1920

—H 673 1921 vinyl —H 566 1922 —(CH₂)₃Cl —H 616 1923 cyclohexylmethyl —H 636 1924

—F 691 1925 vinyl —F 584 1926 —(CH₂)₃Cl —F 634 1927 cyclohexylmethyl —F 654 1928

—CH₃ 687 1929 vinyl —CH₃ 580 1930 —(CH₂)₃Cl —CH₃ 630 1931 cyclohexylmethyl —CH₃ 650 1932 2-BrPh— —H 696 1933

—H 656

TABLE 315

Example No. R₉₄₇ MS (M⁺ + H) 1934 3,5-Cl₂Ph 684 1935

683 1936

682 1937

702 1938

687 1939

681 1940

723 1941 5-isoquinolyl 667 1942 —CH₂CF₃ 622 1943

688 1944

668 1945

635 1946

690 1947

690

TABLE 316

Example MS No. R₉₄₈ R₉₄₉ (M⁺ + H) 1948 —CH₂Cl —H 588 1949

—H 702 1950

—H 660 1951

—H 694 1952

—H 680 1953

—H 726 1954 benzyl —H 630 1955 PhCH═CH— —H 642 1956 —(CH₂)₂CH₃ —H 582 1957 2-BrPh— —F 714 1958

—F 674 1959 3,5-Cl₂Ph —F 702 1960

—F 701 1961

—F 700 1962

—F 720 1963

—F 705 1964

—F 699 1965

—F 741

TABLE 317

Example No. R₉₅₀ MS (M⁺ + H) 1966 5-isoquinolyl 685 1967 —CH₂CF₃ 640 1968

706 1969

686 1970

653 1971

694 1972

708 1973

708 1974 —CH₂Cl 606 1975

720 1976

678 1977

712 1978

698 1979

744 1980 benzyl 648 1981 PhCH═CH— 660

TABLE 318

Example MS No. R₉₅₁ R₉₅₂ (M⁺ + H) 1982 —(CH₂)₂CH₃ —F 600 1983 2-BrPh— —CH₃ 710 1984

—CH₃ 670 1985 3,5-Cl₂Ph —CH₃ 698 1986

—CH₃ 697 1987

—CH₃ 696 1988

—CH₃ 716 1989

—CH₃ 701 1990

—CH₃ 695 1991

—CH₃ 737 1992 5-isoquinolyl —CH₃ 681 1993 —CH₂CF₃ —CH₃ 636 1994

—CH₃ 702 1995

—CH₃ 682 1996

—CH₃ 649

TABLE 319

Example No. R₉₅₃ R₉₅₄ MS (M⁺ + H) 1997

—CH₃ 690 1998

—CH₃ 704 1999

—CH₃ 704 2000 —CH₂Cl —CH₃ 602 2001

—CH₃ 716 2002

—CH₃ 674 2003

—CH₃ 708 2004

—CH₃ 694 2005

—CH₃ 740 2006 benzyl —CH₃ 644 2007 —CHCl₂ —CH₃ 636 2008 PhCH═CH— —CH₃ 656 2009 —(CH₂)₂CH₃ —CH₃ 596 2010 2,3,4-F₃Ph— —H 670 2011 2,3,4-F₃Ph— —F 688 2012 2,3,4-F₃Ph— —CH₃ 684

TABLE 320

Example No. R₉₅₅ R₉₅₆ R₉₅₇ Xb₂₉ ¹H NMR (solvent) δppm 2013 3,4-Cl₂Ph— —CH₃ —H —CO— (CDCl₃) 2.12(3H, s), 2.50-2.52(4H, m), 3.45(2H, s), 3.72(2H, brs), 4.24(2H, brs), 5.95(2H, s), 6.71-6.78(2H, m), 6.85-6.89(2H, m), 7.00(1H, d, J = 8.6 Hz), 7.42(1H, dd, J = 8.6 Hz, 2.5 Hz), 7.52-7.55(3H, m), 7.60(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.70(1H, d, J = 2.6 Hz), 7.79(1H, brs), 9.17(1H, brs). 2014 4-CF₃Ph— —CH₃ —H —CO— (CDCl₃) 2.10(3H, s), 2.50-2.54(4H, m), 3.45(2H, s), 3.70-3.73(2H, m), 4.23(2H, brs), 5.95(2H, s), 6.71-6.78(2H, m), 6.83-6.87(2H, m), 6.99(1H, d, J = 8.6 Hz), 7.42(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.54(1H, d, J = 2.5 Hz), 7.60(1H, dd, J = 8.7 Hz, 3.3 Hz), 7.70(1H, d, J = 3.3 Hz), 7.72(2H, d, J = 8.9 Hz), 7.85(2H, d, J = 8.3 Hz), 9.18(1H, brs). 2015 3,4-Cl₂Ph— —CH₃ —CH₃ —CO— (CDCl₃) 2.12(3H, brs), 2.20-2.50(4H, m), 3.27-3.46(9H, m), 5.95-5.96(2H, m), 6.66- 6.77(3H, m), 6.85-7.04(2H, m), 7.08-7.22(2H, m), 7.51-7.53(2H, m), 7.55-7.72(2H, m), 7.78- 7.80(1H, m). 2016 4-CF₃Ph— —CH₃ —CH₃ —CO— (DMSO-d₆) 2.11(3H, s), 2.19-2.51(4H, m), 3.28-3.71(9H, m), 5.96(2H, s), 6.65-6.78(3H, m), 6.85-7.04(2H, m), 7.08-7.22(2H, m), 7.57- 7.65(1H, m), 7.70-7.73(3H, m), 7.84-7.87(2H, m). 2017 3,4-Cl₂Ph— —H —SO₂CH₃ —CH₂— (CDCl₃) 2.42(4H, brs), 3.20(3H, s), 3.37- 3.39(2H, m), 3.42(2H, s), 3.61(2H, brs), 4.54(2H, s), 5.95(2H, s), 6.70-6.77(2H, m), 6.83(1H, brs), 6.93(1H, d, J = 8.6 Hz), 7.08(2H, d, J = 8.9 Hz), 7.53-7.54(2H, m), 7.58-7.63(3H, m), 7.77(1H, d, J = 2.6 Hz), 7.88(1H, d, J = 1.0 Hz). 2018 4-CF₃Ph— —H —SO₂CH₃ —CH₂— (CDCl₃) 2.42(4H, brs), 3.19(3H, s), 3.37(2H, brs), 3.42(2H, s), 3.61(2H, brs), 4.53(2H, s), 5.95(2H, s), 6.73-6.77(2H, m), 6.83(1H, brs), 6.92(1H, d, J = 8.7 Hz), 7.08(2H, d, J = 8.7 Hz), 7. 59(2H, d, J = 8.7 Hz), 7.61(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.73-7.76(3H, m), 7.87(2H, d, J = 8.6 Hz). 2019 3,4-Cl₂Ph— —CH₃ —SO₂CH₃ —CH₂— (CDCl₃) 2.12(3H, s), 2.42(4H, brs), 3.21(3H, s), 3.38(2H, brs), 3.42(2H, s), 3.61(2H, brs), 4.53(2H, s), 5.95(2H, s), 6.70-6.77(2H, m), 6.83(1H, brs), 6.91(1H, d, J = 8.7 Hz), 6.98(1H, d, J = 8.4 Hz), 7.40-7.50(2H, m), 7.53-7.56(2H, m), 7.60(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.71(1H, d, J = 2.3 Hz), 7.80(1H, dd, J = 1.7 Hz, 0.8 Hz).

TABLE 321

Example No. R₉₅₈ R₉₅₉ R₉₆₀ ¹H NMR (solvent) δppm 2020 4-CF₃Ph— —CH₃ —SO₂CH₃ (CDCl₃) 2.10(3H, s), 2.40-2.42(4H, m), 3.20(3H, s), 3.37(2H, brs), 3.42(2H, s), 3.60(2H, brs), 4.53(2H, s), 5.94(2H, s), 6.69-6.76(2H, m), 6.83(1H, brs), 6.87(1H, d, J = 8.7 Hz), 6.96(1H, d, J = 8.4 Hz), 7.40(1H, d, J = 8.6 Hz), 7.44(1H, brs), 7.59(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.72(2H, d, J = 8.2 Hz), 7.73(1H, d, J = 2.8 Hz), 7.86(2H, d, J = 8.2 Hz). 2021 4-CF₃Ph— —CF₃ —C₂H₅ (DMSO-d₆) 1.11(3H, t, J = 6.9 Hz), 2.25-2.45(4H, m), 3.35-3.55(8H, m), 4.26(2H, s), 5.99(2H, 8), 6.67- 7.04(7H, m), 7.52(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.74(1H, d, J = 2.6 Hz), 7.88-7.98(4H, m), 10.48(1H, brs). 2022

—CF₃ —C₂H₅ (DMSO-d₆) 1.11(3H, t, J = 6.9 Hz), 2.25-2.45(4H, m), 3.35-3.55(8H, m), 4.26(2H, s), 5.99(2H, s), 6.67- 7.03(7H, m), 7.30-7.45(1H, m), 7.52(1H, dd, J = 8.8 Hz, 2.6 Hz), 7.71(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.79(1H, d, J = 2.7 Hz), 7.99-8.05(1H, m), 10.61(1H, brs). 2023 3,4-Cl₂Ph— —CF₃ —CH₃ (DMSO-d₆) 2.20-2.45(4H, m), 2.97(3H, s), 3.40- 3.55(6H, m), 4.34(2H, s), 5.99(2H, s), 6.70-6.80(2H, m), 6.83-6.88(3H m), 6.97(1H, d, J = 8.8 Hz), 7.03- 7.07(1H, m), 7.52(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.63(1H, dd, J = 8.6 Hz, 2.2 Hz), 7.75(1H, d, J = 2.7 Hz), 7.83-7.87(2H, m), 10.39(1H, brs). 2024

—CF₃ —CH₃ (DMSO-d₆) 2.25-2.50(4H, m), 2.97(3H, s), 3.35- 3.55(6H, m), 4.34(2H, s), 5.99(2H, s), 6.74-7.05(7H, m), 7.30-7.45(1H, m), 7.52(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.71(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.80(1H, d, J = 2.7 Hz), 8.00-8.06(1H, m), 10.61(1H, brs). 2025 3,4-Cl₂Ph— —CN —CH₃ (DMSO-d₆) 2.25-2.50(4H, m), 2.94(3H, s), 3.35- 3.50(6H, m), 4.33(2H, s), 5.99(2H, s), 6.74-7.11(7H, m), 7.50-7.65(2H, m), 7.78(1H, d, J = 2.6 Hz), 7.83(1H, d, J = 8.5 Hz), 7.89(1H, d, J = 1.5 Hz), 10.45(1H, brs). 2026 4-CF₃Ph— —OCH₃ —SO₂CH₃ (CDCl₃) 2.43(4H, brs), 3.20(3H, s), 3.38(2H, brs), 3.43(2H, s), 3.61(2H, brs), 3.68(3H, s), 4.54(2H, s), 5.94(2H, s), 6.73-6.76(2H, m), 6.80-6.90(2H, m), 7.04(1H, d, J = 8.4 Hz), 7.15-7.19(1H, m), 7.24- 7.26(1H, m), 7.57(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.70- 7 72(4H, m), 7.85(2H, d, J = 8.2 Hz). 2027 3,4-Cl₂Ph— —OCH₃ —SO₂CH₃ (CDCl₃) 2.43(4H, brs), 3.21(3H, s), 3.37(2H, brs), 3.43(2H, s), 3.61(2H, brs), 3.71(3H, s), 4.54(2H, s), 5.95(2H, s), 6.73-6.77(2H, m), 6.83(1H, s), 6.92(1H, d, J = 8.7 Hz), 7.06(1H, d, J = 8.6 Hz), 7.18(1H, dd, J = 8.4 Hz, 2.3 Hz), 7.25(2H, s), 7.52(2H, s), 7.57(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.70(1H, d, J = 2.6 Hz), 7.81(1H, s).

TABLE 322

Example No. R₉₆₁ R₉₆₂ R₉₆₃ R₉₆₄ R₉₆₅ ¹H NMR (DMSO-d₆) δppm 2028 3,4-Cl₂Ph— —CH₃ —H —CH₃ —CH₃ 1.93(3H, s), 2.16(3H, s), 2.20-2.40(4H, m), 2.63(3H, s), 3.39(2H, s), 3.39- 3.50(4H, m), 3.74(2H, s), 5.99(2H, s), 6.72-6.92(5H, m), 6.98(1H, s), 7.51(1H, dd, J = 8.8 Hz, 2.4 Hz), 7.63(1H, dd, J = 8.5 Hz, 1.4 Hz), 7.73(1H, d, J = 2.6 Hz), 7.82-7.87(2H, m), 10.35(1H, brs). 2029

—CH₃ —H —CH₃ —CH₃ 1.90(3H, s), 2.15(3H, s), 2.25-2.40(4H, m), 2.62(3H, s), 3.38(2H, s), 3.38- 3.50(4H, m), 3.73(2H, s), 5.98(2H, s), 6.72-6.76(2H, m), 6.82-6.88(3H, m), 6.97(1H, s), 7.30-7.45(1H, m), 7.51(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.72(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.78(1H, d, J = 2.8 Hz), 7.98-8.04(1H, m), 10.56(1H, brs). 2030 3,4-Cl₂Ph— —H —CF₃ —H —C₂H₅ 0.92(3H, t, J = 7.1 Hz), 2.20-2.40(4H, m), 3.11(2H, q, J = 7.1 Hz), 3.35- 3.50(6H, m), 3.83(2H, s), 5.98(2H, s), 6.70-6.90(3H, m), 7.05(1H, d, J = 8.8 Hz), 7.32-7.36(2H, m), 7.56-7.75(3H, m), 7.81-7.91(3H, m), 10.48(1H, brs).

Example 2031 N-{4-[4-(4-benzenesulfonylpiperazin-1-yl)phenoxy]phenyl}-3,4-dichlorobenzamide

Melting point: 191-192° C.

The following compounds were produced in the same manner as in Reference Example 292.

TABLE 323

Ex- ample No. R₉₆₆ ¹H NMR (CDCl₃) δppm 2032 —CH₃ 2.41(4H, brs), 3.20(3H, s), 3.36(2H, brs), 3.42(2H, s), 3.59(2H, brs), 3.66(3H, s), 4.50(2H, s), 5.94(2H, s), 6.70-6.76(2H, m), 6.83(1H, s), 6.93(1H, d, J = 8.7 Hz), 6.99-7.04(2H, m), 7.13(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.51(1H, d, J = 2.3 Hz), 7.69(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.95(1H, d, J = 2.1 Hz), 8.12(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.23(1H, d, J = 2.6 Hz), 8.53(1H, s). 2033 —C₂H₅ 1.37(3H, t, J = 7.4 Hz), 2.42(4H, brs), 3.38-3.46(6H, m), 3.60(2H, brs), 3.71(3H, s), 4.53(2H, s), 5.94(2H, s), 6.70-6.77(2H, m), 6.84(1H, s), 6.97(1H, d, J = 8.7 Hz), 7.06(1H, d, J = 8.6 Hz), 7.14-7.18(1H, m), 7.26 (1H, s), 7.55(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.98(1H, d, J = 2.1 Hz), 8.16-8.23(3H, m).

Example 2034 Production of t-butyl 4-{4-[(5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenylcarbamoyl}piperidine-1-carboxylate

To a solution of N-[6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride (1.0 g, 2.24 mmol) in DMF (15 mL) were added, piperidine-1,4-dicarboxylic acid mono-t-butyl ester (510 mg, 2.22 mmol), triethylamine (0.94 mL, 6.74 mmol), 1-hydroxybenzotriazole monohydrate (350 mg, 2.29 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (514 mg, 2.68 mmol) under ice cooling. The resulting solution was then stirred under ice cooling for 1 hour, and at room temperature for 17 hours. This reaction solution was concentrated under reduced pressure. The residue was diluted with water and ethyl acetate, whereupon a white powder was precipitated. The white powder was filtered, then washed with water, and subsequently washed with ethyl acetate, to thereby yield 1.04 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 1.41 (9H, s), 1.35-1.50 (2H, m), 1.70-1.85 (2H, m), 2.40-2.60 (1H, m), 2.63-2.90 (2H, m), 3.90-4.11 (2H, m), 7.03 (1H, d, J=8.9 Hz), 7.06 (2H, d, J=8.9 Hz), 7.62 (2H, d, J=8.9 Hz), 7.84 (1H, d, J=8.5 Hz), 7.94 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.17 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.46 (1H, d, J=2.6 Hz), 9.96 (1H, s), 10.54 (1H, s).

The following compound was produced in the same manner as in Example 2034.

Example 2035 3,4-Dichloro-N-(6-{4-[2-(2,4-dioxothiazolidine-5-yl)acetylamino]phenoxy}pyridin-3-yl)benzamide

¹H NMR (DMSO-d₆) δ 3.07 (1H, dd, J=16.5 Hz, 8.9 Hz), 3.24 (1H, dd, J=16.5 Hz, 4.0 Hz), 4.73 (111, dd, J=9.0 Hz, 4.0 Hz), 7.04 (1H, d, J=8.9 Hz), 7.08 (2H, d, J=8.9 Hz), 7.58 (2H, d, J=8.9 Hz), 7.84 (1H, d, J=8.2 Hz), 7.94 (1H, dd, J=8.2 Hz, 2.0 Hz), 8.18 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.46 (1H, d, J=2.6 Hz), 10.21 (1H, s), 10.53 (1H, s), 12.00 (1H, s).

Example 2036 Production of 3,4-dichloro-N-(6-{4-[(4-piperonylpiperazin-1-ylmethyl]phenoxy}pyridin-3-yl)benzamide

To a solution of 3,4-dichloro-N-[6-(4-piperazin-1-ylmethylphenoxy)pyridin-3-yl]benzamide (300 mg, 0.66 mmol) in DMF (10 mL) were added piperonylic acid (120 mg, 0.72 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg, 0.73 mmol) and 1-hydroxybenzotriazole monohydrate (100 mg, 0.74 mmol) under ice cooling. The resulting reaction solution was stirred overnight at room temperature. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 110 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.46 (4H, brs), 3.53 (2H, s), 3.60 (4H, brs), 5.99 (2H, s), 6.79 (1H, d, J=7.9 Hz), 6.85-6.96 (3H, m), 7.08 (2H, d, J=8.6 Hz), 7.33 (2H, d, J=8.3 Hz), 7.54 (1H, d, J=8.3 Hz), 7.69-7.73 (1H, m), 7.99 (1H, d, J=2.3 Hz), 8.16-8.21 (1H, m), 8.27-8.30 (2H, m).

The following compounds were produced in the same manner as in Example 2036.

TABLE 324

Example No. R₉₆₇ R₉₆₈ Xb₃₀ R₉₆₉ mp (° C.) or ¹H NMR (solvent) δppm 2037 —CF₃ —H —CO—

¹H NMR (DMSO-d₆) 3.52(4H, brs), 3.60(4H, brs), 5.57(1H, s), 7.17(1H, d, J = 8.9 Hz), 7.20(2H, d, J = 8.9 Hz), 7.51(2H, d, J = 8.4 Hz), 7.95(2H, d, J = 8.1 Hz), 8.17(2H, d, J = 8.1 Hz), 8.27(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.55(1H, d, J = 2.6 Hz), 10.69(1H, brs), 11.18(1H, brs), 11.32(1H, brs). 2038 —Cl —Cl —CH₂—

mp 250-251 2039 —CF₃ —H —CH₂— 2-CNPh— mp 189-192 2040 —CF₃ —H —CH₂— 4-pyridyl mp 122-124 2041 —CF₃ —H —CH₂— 3-pyridyl mp 167-168 2042 —CF₃ —H —CH₂— 2-pyridyl mp 189-191 2043 —CF₃ —H —CH₂—

¹H NMR (DMSO-d₆) 2.45(4H, brs), 3.36(2H, s), 3.54-4.18(4H, m), 7.09(3H, d, J = 8.9 Hz), 7.36(2H, d, J = 8.4 Hz), 7.59(1H, brs), 7.72(1H, s), 7.94(2H, d, J = 8.4 Hz), 8.18(2H, d, J = 8.4 Hz), 8.24(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.53(1H, d, J = 2.6 Hz), 10.67(1H, s), 12.48(1H, brs). 2044 —CF₃ —H —CH₂—

¹H NMR (CDCl₃ + CD₃OD) 2.98- 3.15(5H, m), 3.34-3.47(1H, m), 3.61- 3.76(4H, m), 4.18(2H, s), 4.57(1H, dd, J = 10.2 Hz, 3.1 Hz), 7.04(1H, d, J = 8.7 Hz), 7.19(2H, d, J = 8.6 Hz), 7.49(2H, d, J = 8.6 Hz), 7.79(2H, d, J = 8.3 Hz), 8.11(2H, d, J = 8.1 Hz), 8.25 (1H, dd, J = 8.9 Hz, 2.8 Hz) 8.52(1H, d, J = 2.3 Hz). 2045 —CF₃ —H —(CH₂)₃—

¹H NMR (CDCl₃) 1.81-1.89(2H, m), 2.40- 2.45(6H, m), 2.62-2.68(2H, m), 3.61(4H, brs), 5.98(2H, s), 6.76-6.93(4H, m), 7.03(2H, d, J = 8.4 Hz), 7.19(2H, d, J = 8.4 Hz), 7.68(2H, d, J = 8.4 Hz), 7.99(2H, d, J = 8.3 Hz), 8.18-8.23(1H, m), 8.30(1H, d, J = 2.6 Hz), 8.73(1H, s). 2046 —CF₃ —H —(CH₂)₃— 3,4-(CH₃O)₂Ph— ¹H NMR (CDCl₃) 1.78-1.89(2H, m), 2.39- 2.45(6H, m), 2.63-2.68(2H, m), 3.62(4H, brs), 3.85(3H, s), 3.89(3H, s), 6.82- 6.85(1H, m), 6.91-6.95(3H, m), 7.01- 7.06(2H, m), 7.18-7.23(2H, m), 7.70(2H, d, J = 8.2 Hz), 7.99(2H, d, J = 8.2 Hz), 8.20-8.24(1H, m), 8.29(1H, d, J = 2.6 Hz), 8.51(1H, brs).

TABLE 325

Example No. R₉₇₀ R₉₇₁ R₉₇₂ M Form ¹H NMR (solvent) δppm 2047 —CF₃ —H

1 free (DMSO-d₆) 1.94(6H, s), 2.49- 2.51(4H, m), 2.76-2.93(1H, m), 3.17-3.51(7H, m), 4.20(1H, dd, J = 10.4 Hz, 3.0 Hz), 7.09-7.13(3H, m), 7.42 (2H, brs), 7.94(2H, d, J = 8.4 Hz), 8.16-8.26(3H, m), 8.54(1H, d, J = 2.5 Hz), 10.67(1H, s), 11.68 (1H, brs). 2048 —CF₃ —H

1 free (CDCl₃ + CD₃OD) 2.46-2.59(4H, m), 3.16(1H, dd, J = 14.2 Hz, 9.4 Hz), 3.32(4H, brs), 3.51(1H, dd, J = 14.0 Hz, 3.8 Hz), 3.79(2H, brs), 4.50(1H, dd, J = 9.4 Hz, 4.0 Hz), 6.93(1H, d, J = 8.9 Hz), 7.06(2H, d, J = 8.4 Hz), 7.26-7.46(6H, m), 7.72 (2H, d, J = 8.3 Hz), 8.05(2H, d, J = 8J Hz), 8.27 (1H, d, J = 2.1 Hz), 8.33(1H, dd, J = 8.9 Hz, 2.8 Hz). 2049 —CF₃ —H

1 free (DMSO-d₆) 2.49-2.52(4H, m), 3.34-3.40(4H, m), 3.57(2H, s), 7.06-7.10(3H, m), 7.36(2H, d, J = 8.6 Hz), 754(2H, d, J = 8.1 Hz), 7.67(2H, d, J = 8.4 Hz), 7.79(1H, s), 7.94(2H, d, J = 8.6 Hz), 8.15- 8.25(3H, m), 8.51(1H, d, J = 2.8 Hz), 10.64 (1H, s). 2050 —CF₃ —H 4-pyridyl 3 hydro- (DMSO-d₆) 2.04(2H, brs), 2.63- chloride 2.69(2H, m), 3.10-3.59(9H, m), 4.54(1H, brs), 7.05-7.08(3H, m), 7.28(2H, d, J = 8.2 Hz), 7.45(2H, d, J = 4.9 Hz), 7.94(2H, d, J = 8.2 Hz), 8.18-8.26(3H, m), 8.53(1H, d, J = 2.3 Hz), 8.70(2H, d, J = 5.4 Hz), 10.72(1H, s), 11.27(1H, brs). 2051 —Cl —Cl 3,4-F₂Ph— 1 free (CDCl₃) 2.46(4H, brs), 3.47- 3.72(6H, m), 6.91 (1H, d, J = 8.9 Hz), 7.05-7.33(7H, m), 7.50(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.97(1H, d, J = 2.1 Hz), 8.14-8.18(1H, m), 8.28 (1H, d, J = 2.6 Hz), 8.68(1H, s).

TABLE 326 Ex- ample No. Chemical structure mp (° C.) or ¹H NMR 2052

mp 171-173 2053

mp 116-118 2054

mp 133-135 2055

¹H NMR (CDCl₃) δ 2.39 (2H, brs), 2.55 (2H, brs), 3.00 (3H, s), 3.35(2H, brs), 3.51 (2H, s), 3.79(2H, brs), 4.40 (2H, s), 6.82(1H, d, J = 8.9 Hz), 6.99-7.13(4H, m), 7.25- 7.29(5H, m), 7.32 (1H, d, J = 1.8 Hz), 7.39(1H, d, J = 3.3 Hz), 8.68-8.70(2H, m).

Example 2056 Production of N-{6-[4-(4-chloroacetylpiperazino)phenoxy]-3-pyridyl}-4-(trifluoromethyl)benzamide

To a solution of N-[6-(4-piperazinophenoxy)-3-pyridyl]-4-(trifluoromethyl)benzamide (885 mg, 2.00 mmol) in DMF (20 mL) were added triethylamine (0.418 mL, 3.00 mmol) and chloroacetyl chloride (0.191 g, 2.40 mmol), and the resulting reaction solution was stirred for 10 minutes at room temperature. To this reaction solution was added ethyl acetate. The resulting solution was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 1.00 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 3.17 (2H, t, J=5.0 Hz), 3.22 (2H, t, J=5.0 Hz), 3.70 (2H, t, J=5.0 Hz), 3.80 (2H, t, J=5.0 Hz), 6.95 (1H, d, J=9.0 Hz), 6.97 (2H, d, J=9.0 Hz), 7.08 (2H, d, J=9.0 Hz), 7.77 (1H, brs), 7.78 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=8.0 Hz), 8.20 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.26 (1H, d, J=2.5 Hz).

The following compounds were produced in the same manner as in Example 2056.

TABLE 327

Example No. R₉₇₃ R₉₇₄ Xb₃₁ R₉₇₅ mp (° C.) or ¹H NMR (solvent) δppm 2057 —CF₃ —H —CO— 4-CNPh— ¹H NMR (DMSO-d₆) 3.29 3.69(8H, m), 7.14- 7.20(3H, m), 7.49(2H, d, J = 8.6 Hz), 7.63(2H, d, J = 8.1 Hz), 7.93-7.95(4H, m), 8.17(2H, d, J = 8.1 Hz), 8.27(1H, dd, J = 8.9 Hz, 2.4 Hz), 8.55(1H, d, J = 2.4 Hz), 10.66(1H, s). 2058 —CF₃ —H —CO— —CH₃ ¹H NMR (CDCl₃) 2.13(3H, s), 3.35-3.90(8H, m), 7.02(1H, d, J = 8.8 Hz), 7.17(2H, d, J = 8.6 Hz), 7.44(2H, d, J = 8.6 Hz), 7.75(2H, d, J = 8.1 Hz), 8.02(2H, d, J = 8.1 Hz), 8.25(1H, dd, J = 8.8 Hz, 2.5 Hz), 8.33(1H, d, J = 2.5 Hz), 8.38(1H, brs). 2059 —Cl —Cl —CH₂— —Ph ¹H NMR (CDCl₃) 2.08-2.55(4H, m), 3.43- 3.45(2H, m), 3.55(2H, s), 3.79-3.81 (2H, m), 6.96(1H, d, J = 8.9 Hz), 7.07-7.12(2H, m), 7.33-7.46(7H, m), 7.57(1H, d, J = 8.6 Hz), 7.69-7.73(1H, m), 7.94-7.99(2H, m), 8.17- 8.21(1H, m), 8.27(1H, d, J = 2.6 Hz). 2060 —Cl —Cl —CH₂— 4-CNPh— ¹H NMR (CDCl₃) 2.44(2H, brs), 2.58(2H, brs), 3.39(2H, brs), 3.56(2H, s), 3.81(2H, brs), 6.96(1H, d, J = 8.9 Hz), 7.08-7.12(2H, m), 7.34(2H, d, J = 8.4 Hz), 7.48-7.51(2H, m), 7.57(1H, d, J = 8.4 Hz), 7.69-7.77(3H, m), 7.95(1H, brs), 7.98(1H, d, J = 2.0 Hz), 8.14- 8.21(1H, m), 8.27(1H, d, J = 2.3 Hz). 2061 —CF₃ —H —CH₂— 4-CNPh— mp 167-168 2062 —CF₃ —H —CH₂— —Ph ¹H NMR (CDCl₃) 2.41-2.53(4H, m), 3.43(2H, brs), 3.53 (2H, s), 3.78(2H, brs), 6.95(1H, d, J = 8.9 Hz), 7.06-7.11 (2H, m), 7.33-7.41(7H, m), 7.71(2H, d, J = 8.4 Hz), 7.99 (2H, d, J = 8.4 Hz), 8.23(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.31 (1H, d, J = 2.7 Hz), 8.39(1H, s). 2063 —CF₃ —H —CH₂— 3,4-F₂Ph— mp 130-133 2064 —CF₃ —H —CH₂— 3-CNPh— ¹H NMR (CDCl₃) 2.43(2H, brs), 2.56(2H, brs), 3.39(2H, brs), 3.55(2H, s), 3.79(2H, brs), 6.97(1H, d, J = 8.9 Hz), 7.07-7.12(2H, m), 7.32-7.37(2H, m), 7.50-7.77(6H, m), 8.00(2H. d, J = 8.1 Hz), 8.07(1H, brs), 8.23(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.28(1H, d, J = 2.7 Hz). 2065 —CF₃ —H —CH₂— 4-CH₃Ph— mp 193-194 2066 —CF₃ —H —CH₂— 4-ClPh— mp 176-178 2067 —CF₃ —H —CH₂— 4-CH₃OPh— mp 190-191

TABLE 328

Example No. R₉₇₆ R₉₇₇ M ¹H NMR (CDCl₃) δppm 2068 3,4-Cl₂PhCH₂N(CH₃)— —Ph 1 2.38(2H, brs), 2.53(2H, brs), 2.99(3H, s), 3.42(2H, brs), 3.50(2H, s), 3.79(2H, brs), 4.39(2H, s), 6.81(1H, d, J = 8.9 Hz), 6.99- 7.12(4H, m), 7.26-7.39(9H, m), 7.69(1H, d, J = 3.1 Hz). 2069 3,4-Cl₂PhCH₂N(CH₃)— 4-CNPh— 1 2.39(2H, brs), 2.55(2H, brs), 3.01(3H, s), 3.35(2H, brs), 3.51(2H, s), 3.79(2H, brs), 4.40(2H, s), 6.82(1H, d, J = 8.9 Hz), 6.99- 7.13(4H, m), 7.25-7.33(3H, m), 7.39(1H, d, J = 8.1 Hz), 7.48-7.52(2H, m), 7.69-7.73(3H, m). 2070 3,4-Cl₂PhCH₂N(CH₃)— 4-ClPh— 1 2.34-2.59(4H, m), 3.00(3H, s), 3.36(2H, brs), 3.52(2H, s), 3.83(2H, brs), 4.40(2H, s), 6.82(1H, d, J = 8.9 Hz), 6.98-7.13(4H, m), 7.25-7.41(8H, m), 7.70(1H, d, J = 3.3 Hz). 2071 3,4-Cl₂PhCH₂N(CH₃)— 3,4-F₂Ph— 1 2.33-2.57(4H, m), 3.00(3H, s), 3.37-3.51(4H, m), 3.75 (2H, brs), 4.40(2H, s), 6.82(1H, d, J = 8.9 Hz), 7.00-7.32 (10H, m), 7.39(1H, d, J = 8.1 Hz), 7.69(1H, d, J = 3.1 Hz). 2072 4-CF₃PhCONH— —Ph 3 1.78-1.89(2H, m), 2.39-2.49(6H, m), 2.66(2H, t, J = 7.6 Hz), 3.44(2H, brs), 3.79(2H, brs), 6.94(1H, d, J = 8.7 Hz), 7.02- 7.07(2H, m), 7.18-7.23(2H, m), 7.35- 7.42(5H, m), 7.72(2H, d, J = 8.2 Hz), 7.99(2H, d, J = 8.1 Hz), 8.19-8.29(3H, m). 2073 4-CF₃PhCONH— 4-CNPh— 3 1.79-1.90(2H, m), 2.41-2.69(8H, m), 3.39(2H, brs), 3.81 (2H, brs), 6.95(1H, d, J = 8.9 Hz), 7.02-7.07(2H, m), 7.18-7.23(2H, m), 7.49(2H, d, J = 7.9 Hz), 7.69-7.77(4H, m), 8.00(2H, d, J = 8.1 Hz), 8.06(1H, brs), 8.21(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.28(1H, d, J = 2.6 Hz). 2074 4-CF₃PhCONH— 3,4-F₂Ph— 3 1.82-1.87(2H, m), 2.41-2.69(8H, m), 3.47- 3.76(4H, m), 6.95(1H, d, J = 8.7 Hz), 7.02- 7.07(2H, m), 7.11-7.28(5H, m), 7.75(2H, d, J = 8.4 Hz), 7.99-8.06(3H, m), 8.19-8.23 (1H, m), 8.28(1H, d, J = 2.6 Hz).

TABLE 329

Example No. Xb₃₂ Xb₃₃ R₉₇₈ mp (° C.) or ¹H NMR (solvent) δppm 2075

—COPh mp 136-138 2076

4-CH₃OPhCO— mp 161-162 2077

4-CF₃PhCO— mp 143-144 2078

mp 163-165 2079

4-ClPhCO— mp 147-151 2080

—N(CH₃)COPh mp 231-232 2081

—N(CH₃)COCH₂Cl ¹H NMR (CDCl₃) 1.70-1.76(2H, m), 1.80- 1.90(2H, m), 2.80-2.88(2H, m), 2.98(3H, s), 3.56-3.68(2H, m), 4.10 (2H, s), 4.57(1H, m), 6.94-6.99(6H, m), 7.53-7.58(3H, m), 7.69-7.71(2H, m), 7.97(1H, d, J = 2.0 Hz). 2082

—COCH₂Cl ¹H NMR (DMSO-d₆) 3.08(2H, m), 3.14(2H, m), 3.61(4H, m), 4.44(2H, s), 6.93- 7.02(6H, m), 7.71(2H, d, J = 9.0 Hz), 7.82(1H, d, J = 8.5 Hz), 7.93(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1H, d, J = 2.0 Hz), 10.39(1H, s). 2083

—COCH₂Cl ¹H NMR (CDCl₃) 1.66(1H, m), 1.74(1H, m), 1.91-1.98 (2H, m), 2.72-2.77(2H, m), 3.24(1H, m), 3.99(1H, brd, J = 13.0 Hz), 4.11(2H, s), 4.73(1H, brd, J = 13.0 Hz), 6.96 (2H, d, J = 8.5 Hz), 7.02(2H, d, J = 9.0 Hz), 7.15(2H, d, J = 8.5 Hz), 7.56- 7.79(3H, m), 7.71(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.90(1H, brs), 7.98(1H, d, J = 2.0 Hz).

TABLE 330

Example No. R₉₇₉ R₉₈₀ Xb₃₄ Xb₃₅ Xb₃₆ R₉₈₁ mp (° C.) or MS 2084 3,4-Cl₂Ph— —H none none

—N(CH₃)COCH₂Ph MS 616(M⁺) 2085 4-CF₃Ph— —CH₃ —N(CH₃)— —CH₂—

4-CNPhCO— mp 131-132 2086 4-CF₃Ph— —CH₃ —N(CH₃)— —CH₂—

mp 143-145

TABLE 331

Example No. R₉₈₂ Xb₃₇ R₉₈₃ Property 2087 —H

—Ac mp 138-140° C. 2088 —F

—N(CH₃)COCH₂Ph MS 661(M⁺) 2089 —H

—COCH₂Cl ¹H NMR (CDCl₃) δ 2.62(2H, t, J = 7.6 Hz), 2.95(2H, t, J = 7.6 Hz), 3.31-3.73(8H, m), 4.05(2H, s), 6.91(2H, d, J = 8.5 Hz), 6.97(2H, d, J = 8.9 Hz), 7.15(2H, d, J = 8.5 Hz), 7.49-7.60(3H, m), 7.68(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.91(1H, brs), 7.95(1H, d, J = 2.1 Hz).

TABLE 332

Example No. R₉₈₄ mp (° C.) 2090 2-pyridyl 217-218 2091 3-pyridyl 191-192 2092 4-pyridyl 204-205

TABLE 333

Example No. R₉₈₅ mp (° C.) or ¹H NMR (CDCl₃) δppm 2093 —Ph mp 185-186 2094 —CH₂Cl a mixture of the rotational isomers ¹H NMR 2.57(0.4H, brs), 2.65(0.6H, brs), 3.74(0.6H, t, J = 6.0 Hz), 3.85 (0.4H, t, J = 6.0 Hz), 4.13(0.8H, s), 4.15(1.2H, s), 4.22(1.2H, m), 4.25 (0.8H, m), 5.89(0.4H, brs), 6.04(0.6H, brs), 6.98(2H, d, J = 8.5 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.34(2H, dd, J = 8.5 Hz, 4.0 Hz). 7.56- 7.60(3H, m), 7.71(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.89(1H, brs), 7.89(1H, d, J = 2.0 Hz).

Example 2095 Production of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-benzoyloxypiperidine

To a solution of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine (200 mg, 0.44 mmol) in dichloromethane (8 mL) were added with triethylamine (0.091 mL, 0.65 mmol), benzoyl chloride (74 mg, 0.53 mmol) and 4-(dimethylamino)pyridine (3 mg, 0.025 mmol), and the resulting solution was stirred for 2.5 days at room temperature. This reaction solution was purified by silica gel column chromatography (methanol:dichloromethane=7:93), to thereby yield 80 mg of the title compound.

Appearance: White powder

Melting point: 188-190° C.

Example 2096 Production of 3,4-dichloro-N-(6-{4-[[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl](2,2,2-trifluoroacetyl)amino]phenoxy}pyridin-3-yl)benzamide

To a solution of 3,4-dichloro-N-(6-{4-[2-oxo-2-(4-piperonylpiperazin-1-yl)ethylamino]phenoxy}pyridin-3-yl)benzamide (0.152 g, 0.239 mmol) in THF (5 mL) were added triethylamine (0.0500 mL, 0.359 mmol) and trifluoroacetic anhydride (0.0410 mL, 0.287 mmol), and the resulting solution was stirred for 6 hours. Water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to yield a solid. This solid was recrystallized from methanol, to thereby yield 28.8 mg of the title compound.

Appearance: White powder

Melting point: 211-213° C.

The following compound was produced in the same manner as in Example 2096.

Example 2097 N-[6-(4-Acetyl[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl]amino)-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide

¹H NMR (CDCl₃) δ 1.90 (3H, s), 2.28 (2H, brs), 2.38 (2H, brs), 3.37 (4H, brs), 3.49 (2H, brs), 3.67 (3H, s), 4.43 (2H, s), 5.93 (2H, s), 6.68-6.75 (2H, m), 6.82 (1H, s), 6.91-6.97 (2H, m), 7.07-7.10 (2H, m), 7.53 (1H, d, J=8.4 Hz), 7.76 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.05 (1H, d, J=2.0 Hz), 8.20 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.37 (1H, d, J=2.6 Hz), 9.26 (1H, s).

Example 2098 Production of N-[6-(benzoyl{4-[(3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenyl}amino)pyridin-3-yl]-3,4-dichlorobenzamide monooxalate

To a solution of 3,4-dichloro-N-(6-{4-[3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenylamino}-pyridin-3-yl)benzamide (250 mg, 0.395 mmol) in THF (5 mL) were added triethylamine (0.132 mL, 0.949 mmol) and benzoyl chloride (0.0550 mL, 0.474 mmol), and the resulting solution was stirred for 7 hours at room temperature. Water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to yield 0.300 g of a free form. To this free form were added isopropanol (5 mL) and oxalic acid dihydrate (100 mg, 0.793 mmol), and the resulting solution was dissolved under heat. The solvent was evaporated, and the resulting solid was recrystallized from isopropanol, to thereby yield 80.0 mg of the title compound.

Appearance: Yellow powder

Melting point: 140-143° C.

The following compound was produced in the same manner as in Example 2098.

Example 2099 N-[6-(Acetyl{4-[3-oxo-3-(4-piper ylpiperazin-1-yl)propyl]phenyl}amino)pyridin-3-yl]-3,4-dichlorobenzamide

Melting point: 150-165° C.

¹H NMR (DMSO-d₅) δ 1.98 (3H, s), 2.62-2.98 (7H, m), 3.04 (1H, t, J=12.1 Hz), 3.26 (2H, t, J=14.7 Hz), 3.35-3.50 (2H, m), 4.06 (1H, d, J=13.8 Hz), 4.13-4.26 (2H, m), 4.44 (1H, d, J=13.8 Hz), 6.07 (2H, s), 6.95-7.02 (2H, m), 7.20-7.24 (3H, m), 7.28 (2H, d, J=8.3 Hz), 7.52 (1H, d, J=8.9 Hz), 7.85 (1H, d, J=8.4 Hz), 7.96 (1H, dd, J=2.0 Hz, 8.4 Hz), 8.23-8.26 (2H, m), 8.77 (1H, s), 10.77 (1H, s), 11.10 (1H, brs).

Example 2100 Production of 6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}-N-(3,4-dichlorophenyl)nicotinamide

To a solution of 6-{4-[3-(4-piperonylpiperazin-1-yl)-]-oxopropyl]phenoxy}nicotinic acid (1.23 g, 2.5 mmol) in THF (35 mL) was added N,N′-carbonyldiimidazole (540 mg, 3.3 mmol), and the resulting solution was stirred for 30 minutes at room temperature. The resulting reaction solution was concentrated under reduced pressure, and to the residue was added 3,4-dichloroaniline (4.07 g, 25 mmol). The resulting solution was stirred for 3 days at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and the resulting product was recrystallized from diethyl ether, to thereby yield 510 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.33 (4H, brs), 2.59-2.65 (2H, m), 2.91-2.97 (2K, m), 3.40 (4H, brs), 3.59 (2H, s), 5.94 (2H, s), 6.70-6.76 (2H, m), 6.83 (1H, s), 6.96-7.06 (3H, m), 7.20-7.26 (2H, m), 7.40 (1H, d, J=8.6 Hz), 7.50-7.54 (1H, m), 7.86 (1H, d, J=1.8 Hz), 8.18-8.22 (1H, m), 8.44 (1H, brs), 8.66 (1H, brs).

The following compounds were produced in the same manner as in Example 2100.

TABLE 334

Example No. R₉₈₆ Xb₃₈ Xb₃₉ R₉₈₇ mp (° C.) or ¹H NMR (CDCl₃) δppm 2101 3,4-Cl₂Ph— none none benzyl mp 206-207 2102 4-CF₃Ph— none none benzyl ¹H NMR 2.44(4H, brs), 3.53-3.70(6H, m), 6.93(1H, d, J = 8.4 Hz), 7.11- 7.14(2H, m), 7.27-7.40(7H, m), 7.56(2H, d, J = 8.9 Hz), 7.83(2H, d, J = 8.4 Hz), 8.23-8.27(1H, m), 8.71(1H, d, J = 2.4 Hz), 9.39(1H, brs). 2103 4-CF₃Ph— —N(CH₃)— —CH₂— piperonyl ¹H NMR 2.42(4H, brs), 3.03(3H, s), 3.43-3.52(4H, m), 3.60(2H, brs), 4.10(2H, s), 5.95(2H, s), 6.66-6.77(4H, m), 6.85(1H, brs), 6.89(1H, d, J = 8.6 Hz), 6.98(2H, d, J = 6.6 Hz), 7.60(2H, d, J = 8.4 Hz), 7.76(2H, d, J = 8.4 Hz), 8.14(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.33(1H, brs), 8.63(1H, brs). 2104 3,4-Cl₂Ph— —N(CH₃)— —CH₂— piperonyl ¹H NMR 2.42-2.44(4H, m), 3.05(3H, s), 3.44(2H, brs), 3.47-3.57(2H, m), 3.63(2H, brs), 4.11(2H, s), 5.95(2H, s), 6.68-6.74(4H, m), 6.85(1H, brs), 6.92 (1H, d, J = 8.9 Hz), 7.00(2H, d, J = 8.7 Hz), 7.42-7.44(2H, m), 7.80-7.86(1H, m), 7.87(1H, d, J = 2.1 Hz), 8.13(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.63(1H, d, J = 2.1 Hz). 2105 4-CF₃Ph— none none piperonyl ¹H NMR 2.71(4H, brs), 3.46-3.92(6H, m), 5.91(2H, s), 6.65-6.73(2H, m), 6.81(1H, d, J = 1.5 Hz), 7.01 (1H, d, J = 9.1 Hz), 7.14(2H, d, J = 8.7 Hz), 7.43(2H, d, J = 8.7 Hz), 7.60(2H, d, J = 8.6 Hz), 7.82(2H, d, J = 8.6 Hz), 8.29(1H, dd, J = 2.6 Hz, 8.6 Hz), 8.71(1H, d, J = 2.1 Hz), 8.87(1H, brs).

Example 2106 Production of (4-benzylpiperazin-1-yl){4-[5-(3,4-dichlorophenylsulfanyl)pyridin-2-yloxy]phenyl}methanone

To a solution of [4-(5-aminopyridin-2-yloxy)phenyl](4-benzylpiperazin-1-yl)methanone (0.73 g, 1.88 mmol) in concentrated sulfuric acid (0.38 mL)-water (1.1 mL) were added dropwise a solution of sodium nitrate (0.13 g, 1.88 mmol) in water (0.6 mL) under ice cooling. The reaction mixture was stirred for 10 minutes. This reaction mixture was added to a solution of 3,4-dichlorobenzenethiol (0.24 mL, 1.88 mmol) in 2 N aqueous sodium hydroxide (2 mL) under cooling with ice. Water was added to the resulting reaction solution, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (dichloromethane:methanol=80:1), to thereby yield 0.1 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 2.49 (4H, brs), 3.56 (2H, s), 3.56 (2H, brs), 3.78 (2H, brs), 6.99 (1H, d, J=8.9 Hz), 7.20 (2H, d, J=8.7 Hz), 7.25-7.39 (5H, m), 7.46 (1H, dd, J=8.2 Hz, 2.0 Hz), 7.47 (2H, d, J=8.7 Hz), 7.56 (1H, d, J=8.2 Hz), 7.76 (1H, d, J=2.0 Hz), 7.86 (1H, dd, J=8.9 Hz, 2.5 Hz), 8.50 (1H, d, J=2.5 Hz).

The following compound was produced in the same manner as in Example 2106.

Example 2107 2-({4-[5-(3,4-Dichlorophenylsulfanyl)pyridin-2-yloxy]-3-methoxyphenyl}ethylamino)-1-(4-piperonylpiperazin-1-yl)ethanone

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7.0 Hz), 2.43 (4H, t, J=4.9 Hz), 3.43 (2H, s), 3.35-3.50 (2H, m), 3.49-3.60 (2H, m), 3.60-3.70 (2H, m), 3.73 (3H, s), 4.05 (2H, s), 5.95 (2H, s), 6.22 (1H, dd, J=8.9 Hz, 2.7 Hz), 6.35 (1H, d, J=2.7 Hz), 6.70-6.76 (2H, m), 6.85 (1H, s), 6.90 (1H, d, J=9.0 Hz), 6.98 (1H, d, J=8.8 Hz), 7.46 (1H, dd, J=8.2 Hz, 2.0 Hz), 7.55 (1H, d, J=8.2 Hz), 7.75 (1H, d, J=2.0 Hz), 7.78 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.49 (1H, d, J=2.5 Hz).

Example 2108 Production of 1-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3-(3,4-dichlorophenyl)urea

To a solution of 3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (600 mg, 1.3 mmol) in toluene (20 mL) were added ethyldiisopropylamine (0.454 mL, 2.6 mmol) and 3,4-dichlorophenylisocyanate (270 mg, 1.4 mmol), and the resulting solution was stirred for 1 day under reflux. The reaction solution was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=1:19), and then recrystallized from ethyl acetate to thereby yield 280 mg of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 2.37-2.39 (4H, m), 2.61-2.67 (2H, m), 2.89-2.94 (2H, m), 3.41-3.47 (4H, m), 3.61-3.65 (2H, m), 5.94 (2H, s), 6.69-6.83 (4H, m), 6.95 (2H, d, J=8.4 Hz), 7.10-7.26 (4H, m), 7.49 (1H, d, J=2.3 Hz), 7.93-7.96 (2H, m), 8.15 (1H, s), 8.21 (1H, s).

The following compounds were produced in the same manner as in Example 2108.

TABLE 335

Example No. R₉₈₈ ¹H NMR (solvent) δppm 2109

(DMSO-d₆) 1.13(3H, t, J = 6.9 Hz), 2.20-2.60(1H, m), 2.75-3.20(2H, m), 3.20-3.65(7H, m), 3.64(3H, s), 4.05- 4.52(4H, m), 6.07(2H, brs), 6.10(1H, dd, J = 8.8 Hz, 2.7 Hz), 6.27(1H, brs), 6.80(1H, d, J = 8.6 Hz), 6.84(1H, d, J = 8.6 Hz), 7.01(2H, brs), 7.19(1H, brs), 7.33(1H, dd, J = 8.9 Hz, 2.6 Hz), 7.51(1H, d, J = 8.9 Hz), 7.85(1H, dd, J = 8.9 Hz, 2.6 Hz), 7.86(1H, d, J = 2.6 Hz), 8.07(1H, d, J = 2.6 Hz), 8.94(1H, s), 9.28(1H, s). 2110

(CDCl₃) 1.14(3H, t, J = 7.0 Hz), 2.35- 2.55(4H, m), 3.38(2H, q, J = 7.0 Hz), 3.44(2H, s), 3.45-3.55(2H, m), 3.60(3H, s), 3.60-3.75(2H, m), 4.02(2H, s), 5.95(2H, s), 6.60-6.80(4H, m), 6.85(1H, s), 6.92(1H, d, J = 8.9 Hz), 7.00- 7.15(2H, m), 7.22(1H, d, J = 8.7 Hz), 7.45(1H, d, J = 2.3 Hz), 7.75-7.85(2H, m), 7.95(1H, s), 7.97(1H, s). 2111

(CDCl₃) 1.09(3H, t, J = 7.1 Hz), 2.35- 2.45(4H, m), 3.10(2H, q, J = 7.1 Hz), 3.43(2H, s), 3.55-3.65?(4H, m), 3.85(2H, s), 5.95(2H, s), 6.70-6.80(2H, m), 6.85(1H, s), 6.90(1H, d, J = 8.8 Hz), 7.05-7.35(4H, m), 7.46(1H, d, J = 8.8 Hz), 7.53(1H, d, J = 2.4 Hz), 7.79(1H, brs), 7.85(1H, brs), 7.93(1H, d, J = 2.6 Hz), 7.99(1H, dd, J = 8.8 Hz, 2.8 Hz). 2112

(CDCl₃) 1.44(9H, s), 1.96(3H, s), 2.10- 2.30(2H, m), 3.42-3.61(2H, m), 3.62- 3.78(2H, m), 4.04(2H, s), 6.58(1H, d, J = 8.8 Hz), 6.60(1H, d, J = 8.5 Hz), 6.91(1H, dd, J = 2.6 Hz, 8.5 Hz), 7.00(1H, d, J = 2.6 Hz), 7.31(1H, d, J = 8.8 Hz), 7.36(1H, dd, J = 2.3 Hz, 8.8 Hz), 7.69(1H, d, J = 2.3 Hz), 7.79(1H, dd, J = 2.8 Hz, 8.8 Hz), 7.91(1H, d, J = 2.8 Hz), 7.93(1H, s), 8.05(1H, s).

Example 2113 Production of 4-piperonylpiperazine-1-carboxylic acid {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}amide hydrochloride

To a solution of {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}-carbamic acid phenyl ester (320 mg, 0.65 mmol) in DMF (4 mL) was added 1-piperonylpiperazine (285 mg, 1.29 mmol), and the resulting solution was stirred for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=25:1). The obtained residue was dissolved in a mixed solvent of ethanol-ethyl acetate. To the resulting solution was added a solution of 4 N hydrogen chloride in ethyl acetate to bring the pH to 3. The precipitated white powder was then filtered off and washed with ethanol, to thereby yield 330 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.85-3.09 (2H, m), 3.20-3.50 (4H, m), 4.12-4.38 (4H, m), 6.08 (2H, s), 7.02 (2H, d, J=9.0 Hz), 6.93-7.12 (3H, m), 7.28 (1H, d, 1.5 Hz), 7.49 (2H, d, J=9.0 Hz), 7.83 (1H, d, J=8.5 Hz), 7.97 (1H, dd, 8.5 Hz, 2.0 Hz), 8.19 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.25 (1H, d, J=2.0 Hz), 8.50 (1H, d, J=2.6 Hz), 8.92 (1H, s), 10.63 (1H, s).

The following compound was produced in the same manner as in Example 2113.

Example 2114 4-Benzylpiperazine-1-carboxylic acid {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}amide hydrochloride

¹H NMR (DMSO-d₆) δ 2.90-3.20 (2H, m), 3.22-3.45 (4H, m), 4.27 (2H, d, J=13.6 Hz), 4.35 (2H, d, J=5.0 Hz), 7.02 (1H, d, J=8.9 Hz), 7.03 (2H, d, J=8.9 Hz), 7.41-7.52 (3H, m), 7.48 (2H, d, J=8.9 Hz), 7.55-7.69 (2H, m), 7.84 (1H, d, J=8.4 Hz), 7.97 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.19 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.25 (1H, d, J=2.0 Hz), 8.49 (1H, d, J=2.6 Hz), 8.90 (1H, s), 10.62 (1H, s).

Example 2115 Production of 2-[(4-{5-[(3,4-dichlorobenzylidene)amino]pyridin-2-yloxy}phenyl)methylamino]-1-(4-piperonylpiperazin-1-yl)ethanone

2-{[(4-(5-aminopyridin-2-yloxy)phenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone (7.80 g, 16.4 mmol) was dissolved in methanol (400 mL), and to the resulting solution was added 3,4-dichlorobenzaldehyde (2.87 g, 16.4 mmol).

This solution was refluxed for 16 hours. The resulting reaction solution was concentrated under reduced pressure, to thereby yield 10.4 g of the title compound.

Appearance: Brown oil

¹H NMR (CDCl₃) δ 2.44 (4H, brs), 3.03 (3H, s), 3.44-3.45 (2H, m), 3.50 (2H, brs), 3.63 (2H, brs), 4.09 (2H, s), 5.94 (2H, s), 6.65-6.77 (4H, m), 6.84-6.88 (2H, m), 7.03 (2H, d, J=9.1 Hz), 7.54 (1H, d, J=8.3 Hz), 7.58 (1H, dd, J=8.9 Hz, 2.8 Hz), 7.70 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.00 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=2.8 Hz), 8.39 (1H, s).

The following compounds were produced in the same manner as in Example 2115.

TABLE 336

Example No. R₉₈₉ R₉₀₀ R₉₉₁ Xb₄₀ M ¹H NMR (solvent) δppm 2116 3,4-Cl₂Ph— —H benzyl none 0 (DMSO-d₆) 2.41(4H, brs), 3.34-3.51(6H, m), 7.19 (1H, d, J = 8.7 Hz), 7.20(2H, d, J = 7.9 Hz), 7.29-7.33(5H, m), 7.45(2H, d, J = 7.9 Hz), 7.81(1H, d, J = 8.3 Hz), 7.91-7.96(2H, m), 8.15(1H, brs), 8.18 (1H, d, J = 2.6 Hz), 8.75(1H, s). 2117 3,4-Cl₂Ph— —H benzyl none 2 (DMSO-d₆) 2.30(4H, brs), 2.60-2.62 (2H, m), 2.79-2.85(2H, m), 3.44-3.48 (6H, m), 7.05(2H, d, J = 8.4 Hz), 7.09 (1H, d, J = 8.7 Hz), 7.25-7.36 (7H, m), 7.81(1H, d, J = 8.2 Hz), 7.88-7.93(2H, m), 8.13-8.14 (2H, m), 8.74(1H, s). 2118 4-CF₃Ph— —H benzyl none 0 (CDCl₃) 2.47(4H, brs), 3.55(2H, brs), 3.55(2H, s), 3.79(2H, brs), 7.00(1H, d, J = 8.7 Hz), 7.18(2H, d, J = 8.6 Hz), 7.22- 7.40(5H, m), 7.47(2H, d, J = 8.6 Hz), 7.67(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.74(2H, d, J = 8.1 Hz), 8.03(2H, d, J = 8.1 Hz), 8.14(1H, d, J = 2.6 Hz), 8.54(1H, s). 2119 4-CF₃Ph— —H piperonyl —N(CH₃)— 1 (CDCl₃) 2.45(4H, brs), 3.04(3H, s), 3.45- 3.51(4H, m), 3.65(2H, s), 4.09(2H, s), 5.95(2H, s), 6.71-6.74 (4H, m), 6.86- 6.89(2H, m), 7.04(2H, d, J = 9.1 Hz), 7.61(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.73(2H, d, J = 8.3 Hz), 8.01(2H, d, J = 8.4 Hz), 8.14(1H, d, J = 2.6 Hz), 8.53(1H, s). 2120 4-CF₃Ph— —F benzyl none 0 (CDCl₃) 2.49(4H, brs), 3.43-3.75(6H, m), 7.07(1H, d, J = 8.6 Hz), 7.29-7.34(8H, m), 7.69(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.74(2H, d, J = 8.3 Hz), 8.02(2H, d, J = 8.3 Hz), 8.05(1H, d, J = 2.6 Hz), 8.53(1H, s). 2121 3,4-Cl₂Ph— —H piperonyl —N(CH₃)— 2 (CDCl₃) 2.34-2.41(4H, m), 2.55-2.61(2H, m), 2.95 (3H, s), 3.41(4H, brs), 3.61- 3.65(2H, m), 3.68-3.76 (2H, m), 5.94(2H, s), 6.70-6.77(4H, m), 6.84(1H, d, J = 1.0 Hz), 6.89(1H, dd, J = 8.7 Hz, 0.5 Hz), 7.04(2H, d, J = 9.2 Hz), 7.55(1H, d, J = 8.3 Hz), 7.60(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.71(1H, dd, J = 8.3 Hz, 2.0 Hz), 8.01(1H, d, J = 1.8 Hz), 8.11(1H, dd, J = 2.8 Hz, 0.5 Hz), 8.40(1H, brs). 2122 4-CF₃Ph— —H piperonyl —N(CH₃)— 2 (CDCl₃) 2.34-2.41(4H, m), 2.55-2.61 (2H, m), 2.95 (3H, s), 3.39-3.42(4H, m), 3.61- 3.64(2H, m), 3.68-3.76(2H, m), 5.94(2H, s), 6.70-6.77(4H, m), 6.84(1H, d, J = 0.8 Hz), 6.90(1H, dd, J = 8.7 Hz, 0.7 Hz), 7.05(2H, d, J = 9.2 Hz), 7.63(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.73(2H, d, J = 8.3 Hz), 8.01(2H, d, J = 8.6 Hz), 8.13(1H, dd, J = 2.8 Hz, 0.7 Hz), 8.53(1H, brs).

TABLE 337

Example No. R₉₉₂ R₉₉₃ ¹H NMR (CDCl₃) δppm 2123 3,4-Cl₂Ph— —H 2.43(4H, brs), 3.22(3H, s), 3.38(2H, brs), 3.43(2H, s), 3.62(2H, brs), 4.55(2H, s), 5.95(2H, s), 6.74(2H, brs), 6.84(1H, brs), 7.01(1H, d, J = 8.6 Hz), 7.15(2H, d, J = 8.7 Hz), 7.57(1H, d, J = 8.3 Hz), 7.61-7.68(3H, m), 7.72(1H, dd, J = 8.3 Hz, 1.8 Hz), 8.03(1H, d, J = 1.8 Hz), 8.11(1H, d, J = 2.8 Hz), 8.42(1H, brs). 2124 3,4-Cl₂Ph— —CH₃ 2.20(3H, s), 2.42-2.43(4H, m), 3.23(3H, s), 3.38(2H, brs), 3.43(2H, s), 3.62(2H, brs), 4.54(2H, s), 5.94(2H, s), 6.70- 6.77(2H, m), 6.84(1H, brs), 6.97(1H, dd, J = 8.7 Hz, 0.5 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.43-7.49(2H, m), 7.55(1H, d, J = 8.2 Hz), 7.62-7.66(1H, m), 7.69-7.74(1H, m), 8.01(1H, d, J = 2.0 Hz), 8.07(1H, d, J = 2.1 Hz), 8.40(1H, brs). 2125 4-CF₃Ph— —CH₃ 2.20(3H, s), 2.41-2.43(4H, m), 3.23(3H, s), 3.38(2H, brs), 3.43(2H, s), 3.60(2H, brs), 4.55(2H, s), 5.95(2H, s), 6.73- 6.74(2H, m), 6.84(1H, brs), 6.98(1H, d, J = 8.7 Hz), 7.05(1H, d, J = 8.4 Hz), 7.43-7.49(2H, m), 7.65-7.75(3H, m), 8.00-8.10(3H, m), 8.53(1H, brs). 2126 4-CF₃Ph— —OCH₃ 2.43(4H, brs), 3.24(3H, s), 3.39(2H, brs), 3.43(2H, s), 3.63(2H, brs), 3.77(3H, s), 4.57(2H, s), 5.94(2H, s), 6.73-6.77(2H, m), 6.84(1H, s), 7.02(1H, d, J = 8.6 Hz), 7.13(1H, d, J = 8.4 Hz), 7.22(1H, dd, J = 8.4 Hz, 2.3 Hz), 7.30(1H, d, J = 2.3 Hz), 7.66(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.73(2H, d, J = 8.1 Hz), 8.01(2H, d, J = 8.1 Hz), 8.08(1H, d, J = 2.5 Hz), 8.53(1H, s).

TABLE 338

Example No. R₉₉₄ R₉₉₅ ¹H NMR (solvent) δppm 2127 3,4-Cl₂Ph— —H (CDCl₃) 2.20(3H, s), 2.49-2.55(4H, m), 3.45(2H, s), 3.71- 3.75(2H, m), 4.25-4.29(2H, m), 5.95(2H, s), 6.75(2H, brs), 6.86(1H, brs), 6.92(1H, d, J = 8.6 Hz), 7.06(1H, d, J = 8.6 Hz), 7.44(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.53-7.65(3H, m), 7.70(1H, dd, J = 8.2 Hz, 2.0 Hz), 8.01(1H, d, J = 1.8 Hz), 8.07(1H, d, J = 2.8 Hz), 8.40(1H, brs), 9.17(1H, brs). 2128 4-CF₃Ph— —H (CDCl₃) 2.20(3H, s), 2.49-2.55(4H, m), 3.45(2H, s), 3.71- 3.75(2H, m), 4.25-4.28(2H, m), 5.95(2H, s), 6.75(2H, brs), 6.86(1H, brs), 6.93(1H, d, J = 8.7 Hz), 7.07(1H, d, J = 8.7 Hz), 7.45(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.58(1H, d, J = 2.5 Hz), 7.65(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.73(2H, d, J = 8.2 Hz), 8.01(2H, d, J = 8.1 Hz), 8.10(1H, d, J = 2.8 Hz), 8.53(1H, s), 9.19(1H, brs). 2129 3,4-Cl₂Ph— —CH₃ a mixture of the rotational isomers (DMSO-d₆) 2.10-2.44(7H, m), 3.16-3.57(9H, m), 5.96- 5.99(2H, m), 6.67-6.89(3H, m), 7.09-7.26(3H, m), 7.29- 7.38(1H, m), 7.81(1H, d, J = 8.41 Hz), 7.89-7.96(2H, m), 8.10-8.15(2H, m), 8.74(1H, s). 2130 4-CF₃Ph— —CH₃ a mixture of the rotational isomers (DMSO-d₆) 2.11-2.44(7H, m), 3.18-3.57(9H, m), 5.96- 6.00(2H, m), 6.67-6.90(3H, m), 7.09-7.27(3H, m), 7.29- 7.38(1H, m), 7.90(2H, d, J = 8.24 Hz), 7.95-8.00(1H, m), 8.11-8.16(3H, m), 8.85(1H, s).

TABLE 339

Example No. R₉₉₆ R₉₉₇ ¹H NMR (CDCl₃) δppm 2131 —H

1.46(9H, s), 2.41-2.45(4H, m), 3.43-3.47(4H, m), 3.53(2H, s), 6.96(1H, d, J = 8.7 Hz), 7.08- 7.14(2H, m), 7.36(2H, d, J = 8.4 Hz), 7.55(1H, d, J = 8.2 Hz), 7.63(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.71(1H, dd, J = 8.2 Hz, 2.0 Hz), 8.01(1H, d, J = 1.8 Hz), 8.11-8.12(1H, m), 8.41(1H, s). 2132 —CH₃

2.19(3H, s), 3.12(1H, dd, J = 14.0 Hz, 9.9 Hz), 3.55(1H, dd, J = 14.0 Hz, 3.8 Hz), 4.54(1H, dd, J = 9.9 Hz, 3.8 Hz), 6.95(1H, d, J = 8.7 Hz), 7.04(1H, d, J = 8.1 Hz), 7.12(1H, dd, J = 8.1 Hz, 2.1 Hz), 7.16(1H, d, J = 2.1 Hz), 7.56(1H, d, J = 8.4 Hz), 7.64(1H, dd, J = 8.7 Hz, 2.3 Hz), 7.71(1H, dd, J = 8.4 Hz, 1.8 Hz), 8.02(1H, d, J = 1.8 Hz), 8.08(1H, d, J = 2.3 Hz), 8.18 (1H, brs), 8.41(1H, s).

Example 2133 Production of 3-({4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}methylamino)-1-(4-piperonylpiperazin-1-yl)propane-1-one

3-[(4-{5-(3,4-dichlorobenzylidene)pyridin-2-yloxy}phenyl)methylamino]-1-(4-piperonylpiperazin-1-yl)propane-1-one (3.88 g, 6.0 mmol) was dissolved in a mixed solvent of methanol (150 mL) and THF (50 mL). To the resulting solution was slowly added odium borohydride (1.13 g, 30.0 mmol) and that resulting solution was stirred for 13 hours at room temperature. This reaction solution was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=40:1), to thereby yield 3.60 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.32-2.39 (4H, m), 2.52-2.57 (2H, m), 2.91 (3H, s), 3.36-3.40 (4H, m), 3.59-3.63 (2H, m), 3.66-3.71 (2H, m), 3.97 (1H, brs), 4.27 (2H, d, J=5.0 Hz), 5.94 (2H, s), 6.65-6.76 (5H, m), 6.83 (1H, d, J=1.0 Hz), 6.94 (1H, dd, J=8.9 Hz, 3.0 Hz), 6.97 (2H, d, J=9.2 Hz), 7.18 (1H, dd, J=8.3 Hz, 2.0 Hz), 7.40 (1H, d, J=8.4 Hz), 7.45 (1H, d, J=2.0 Hz), 7.56 (1H, d, J=2.5 Hz); MS 647 (M⁺).

The following compounds were produced in the same manner as in Example 2133.

TABLE 340

Example No. R₉₉₈ R₉₉₉ Xb₄₁ M ¹H NMR (solvent) δppm 2134 4-CF₃Ph— piperonyl —N(CH₃)— 1 (CDCl₃) 2.42(4H, brs), 2.99(3H, s), 3.43- 3.49(4H, m), 3.62(2H, brs), 4.04(2H, s), 4.37(2H, s), 5.95(2H, s), 6.67-6.75(5H, m), 6.86(1H, brs), 6.92-6.97(3H, m), 7.47(2H, d, J = 7.9 Hz), 7.58-7.61(3H, m). 2135 4-CF₃Ph— piperonyl —N(CH₃)— 2 (CDCl₃) 2.32-2.39(4H, m), 2.52-2.57(2H, m), 2.91(3H, s), 3.36-3.39(4H, m), 3.59-3.63(2H, m), 3.66-3.71(2H, m), 4.00(1H, brs), 4.37(2H, d, J = 4.3 Hz), 5.94(2H, s), 6.66- 6.76(5H, m), 6.83(1H, d, J = 1.0 Hz), 6.95(1H, dd, J = 8.9 Hz, 3.0 Hz), 6.97(2H, d, J = 9.1 Hz), 7.46(2H, d, J = 8.1 Hz), 7.57- 7.61(3H, m). 2136 3,4-Cl₂Ph— piperonyl —N(CH₃)— 1 (CDCl₃) 2.39-2.43(4H, m), 2.99(3H, s), 3.42(2H, brs), 3.46-3.50(2H, m), 3.60- 3.62(2H, m), 3.97(1H, t, J = 5.8 Hz), 4.05(2H, s), 4.26(2H, d, J = 5.8 Hz), 5.95(2H, s), 6.65-6.77(5H, m), 6.85(1H, brs), 6.93(1H, dd, J = 8.6 Hz, 3.1 Hz), 6.96(2H, d, J = 9.1 Hz), 7.18(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.40(1H, d, J = 8.3 Hz), 7.45(1H, d, J = 2.1 Hz), 7.57(1H, d, J = 2.8 Hz) 2137 3,4-Cl₂Ph— benzyl none 2 (DMSO-d₆) 2.26-2.28(4H, m), 2.57(2H, t, J = 7.9 Hz), 2.76(2H, t, J = 7.9 Hz), 3.40- 3.46(6H, m), 4.28(2H, d, J = 5.9 Hz), 6.36(1H, t, J = 6.1 Hz), 6.77(1H, d, J = 8.7 Hz), 6.85(2H, d, J = 8.3 Hz), 7.09(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.17(2H, d, J = 8.4 Hz), 7.24-7.37(6H, m), 7.50(1H, d, J = 3.0 Hz), 7.58(1H, d, J = 8.3 Hz), 7.62 (1H, d, J = 1.8 Hz). 2138 3,4-Cl₂Ph— benzyl none 0 (DMSO-d₆) 2.38(4H, brs), 3.33-3.50(6H, m), 4.30(2H, d, J = 6.3 Hz), 6.47(1H, t, J = 6.3 Hz), 6.87(1H, d, J = 3.7 Hz), 6.97(2H, d, J = 8.6 Hz), 7.12(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.25-7.39(8H, m), 7.56(1H, d, J = 3.0 Hz), 7.58-7.64(2H, m). 2139 4-CF₃Ph— benzyl none 0 (CDCl₃) 2.45(4H, brs), 3.52(2H, brs), 3.53(2H, s), 3.73 (2H, brs), 4.16(1H, brs), 4.41(2H, s), 6.80(1H, d, J = 8.7 Hz), 6.99(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.03(2H, d, J = 8.5 Hz), 7.20-7.37(5H, m), 7.38(2H, d, J = 8.5 Hz), 7.48(2H, d, J = 8.1 Hz), 7.61(2H, d, J = 8.1 Hz), 7.64 (1H, d, J = 3.0 Hz).

TABLE 341

Example No. R₁₀₀₀ R₁₀₀₁ ¹H NMR (CDCl₃) δppm 2140 3,4-Cl₂Ph— —H 2.41(4H, brs), 3.19(3H, s), 3.33-3.35(2H, m), 3.42(2H, s), 3.60(2H, brs), 4.08(1H, brs), 4.30(2H, d, J = 5.3 Hz), 4.50(2H, s), 5.95(2H, s), 6.73-6.74(2H, m), 6.80-6.84(2H, m), 6.99(1H, dd, J = 8.6 Hz, 3.1 Hz), 7.02(2H, d, J = 8.7 Hz), 7.20(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.42(1H, d, J = 8.3 Hz), 7.66(1H, d, J = 2.1 Hz), 7.54(2H, d, J = 8.9 Hz), 7.60(1H, d, J = 2.8 Hz). 2141 3,4-Cl₂Ph— —CH₃ 2.19(3H, s), 2.41(4H, brs), 3.19(3H, s), 3.35(2H, brs), 3.41(2H, s), 3.60(2H, brs), 4.07-4.15(1H, m), 4.27(2H, s), 4.50(2H, s), 5.93(2H, s), 6.69-6.78(3H, m), 6.83(1H, brs), 6.88(1H, d, J = 8.6 Hz), 6.98(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.17-7.20(1H, m), 7.34-7.44(4H, m), 7.53(1H, d, J = 3.0 Hz). 2142 4-CF₃Ph— —CH₃ 2.20(3H, s), 2.41(4H, brs), 3.19(3H, s), 3.35-3.37(2H, m), 3.41(2H, s), 3.60-3.62(2H, m), 4.15(1H, brs), 4.38(2H, s), 4.50(2H, s), 5.94(2H, s), 6.73(2H, brs), 6.76(1H, d, J = 8.7 Hz), 6.83(1H, brs), 6.88(1H, d, J = 8.6 Hz), 7.00(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.36(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.42(1H, d, J = 2.5 Hz), 7.47(2H, d, J = 8.1 Hz), 7.56(1H, d, J = 2.8 Hz), 7.59(2H, d, J = 8.1 Hz). 2143 4-CF₃Ph— —OCH₃ 2.41(4H, brs), 3.21(3H, s), 3.36(2H, brs), 3.42(2H, s), 3.60(2H, brs), 3.76(3H, s), 4.09(1H, brs), 4.37(2H, s), 4.52(2H, s), 5.94(2H, s), 6.70-6.83(4H, m), 6.97-7.02(2H, m), 7.12-7.16 (1H, m), 7.23-7.26(1H, m), 7.44-7.60(5H, m).

TABLE 342

Example No. R₁₀₀₂ R₁₀₀₃ ¹H NMR (solvent) δ ppm 2144 3,4-Cl₂Ph— —H (CDCl₃) 2.17 (3H, s), 2.48-2.53 (4H, m), 3.44 (2H, s), 3.69- 3.73 (2H, m), 3.97 (1H, brs), 4.23-4.27 (4H, m), 5.95 (2H, s), 6.70-6.74 (3H, m), 6.85 (1H, brs), 6.94 (1H, d, J = 8.7 Hz), 6.96 (1H, dd, J = 8.7 Hz, 3.1 Hz), 7.18 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.36 (1H, dd, J = 8.7 Hz, 2.5 Hz), 7.40 (1H, d, J = 8.2 Hz), 7.45 (1H, d, J = 2.1 Hz), 7.51 (1H, d, J = 2.3 Hz), 7.55 (1H, d, J = 3.0 Hz), 9.11 (1H, brs). 2145 4-CF₃Ph— —H (CDCl₃) 2.19 (3H, s), 2.43-2.53 (4H, m), 3.44 (2H, s), 3.70- 3.73 (2H, m), 4.00 (1H, brs), 4.23-4.27 (2H, m), 4.37 (2H, s), 5.95 (2H, s), 6.72 (1H, d, J = 8.7 Hz), 6.74-6.77 (2H, m), 6.85 (1H, brs), 6.94 (1H, d, J = 8.7 Hz), 6.97 (1H, dd, J = 8.7 Hz, 3.1 Hz), 7.37 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.47 (2H, d, J = 8.4 Hz), 7.51 (1H, d, J = 2.5 Hz), 7.57 (1H, d, J = 3.1 Hz), 7.60 (2H, d, J = 8.1 Hz), 9.11 (1H, brs). 2146 3,4-Cl₂Ph— —CH₃ a mixture of the rotational isomers (DMSO-d₆) 2.25-2.42 (7H, m), 3.22-3.55 (9H, m), 4.27 (2H, d, J = 6.27 Hz), 5.77-5.99 (2H, m), 6.38 (1H, t, J = 6.27 Hz), 6.65- 6.90 (5H, m), 7.06-7.14 (2H, m), 7.22-7.28 (1H, m), 7.32-7.36 (1H, m), 7.46 (1H, d, J = 2.80 Hz), 7.56-7.61 (2H, m). 2147 4-CF₃Ph— —CH₃ a mixture of the rotational isomers (DMSO-d₆) 2.24-2.41 (7H, m), 3.20-3.54 (9H, m), 4.34-4.36 (2H, m), 5.95-5.98 (2H, m), 6.38-6.41 (1H, m), 6.65-6.88 (5H, m), 7.03-7.13 (2H, m), 7.21-7.27 (1H, m), 7.45 (1H, d, J = 2.64 Hz), 7.55 (2H, d, J = 7.75 Hz), 7.67 (2H, d, J = 7.75 Hz).

TABLE 343

Example No. R₁₀₀₄ R₁₀₀₅ ¹H NMR (CDCl₃) δ ppm 2148 —H

1.45 (9H, s), 2.37-2.40 (4H, m), 3.40-3.44 (4H, m), 3.47 (2H, s), 4.28 (2H, s), 6.77 (1H, d, J = 8.7 Hz), 6.95-7.01 (3H, m), 7.17-7.21 (1H, m), 7.26-7.29 (2H, m), 7.41 (1H, d, J = 8.1 Hz), 7.45 (1H, d, J = 1.8 Hz), 7.60 (1H, d, J = 3.0 Hz). 2149 —CH₃

2.19 (3H, s), 3.05 (1H, dd, J = 14.0 Hz, 10.0 Hz), 3.50 (1H, dd, J = 14.0 Hz, 3.8 Hz), 4.02 (1H, brs), 4.27 (2H, s), 4.49 (1H, dd, J = 10.0 Hz, 3.8 Hz), 6.73 (1H, d, J = 8.7 Hz), 6.99 (1H, d, J = 8.2 Hz), 6.97 (1H, dd, J = 8.7 Hz, 2.9 Hz), 7.02 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.09 (1H, d, J = 2.0 Hz), 7.18 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.41 (1H, d, J = 8.2 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.55 (1H, d, J = 2.9 Hz), 8.61 (1H, brs).

Example 2150 Production of 1-(4-benzylpiperazin-1-yl)-3-(4-{5-(piperonylamino)pyridin-2-yloxy}phenyl)propane-1-one

3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (1.04 g, 2.5 mmol) was dissolved in methanol (25 mL). To the resulting solution was added piperonal (0.39 g, 2.63 mmol), and this solution was refluxed overnight. The resulting reaction solution was cooled with ice, and then sodium borohydride (0.28 g, 7.50 mmol) was added. The resulting solution was stirred for 2 hours at room temperature. This reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (ethyl acetate), to thereby yield 0.80 g of the title compound.

Appearance: Yellow oil

¹H NMR (DMSO-d₆) δ 2.28 (4H, brs), 2.57 (2H, t, J=7.9 Hz), 2.76 (2H, t, J=7.9 Hz), 3.40-3.46 (6H, m), 4.15 (2H, d, J=6.1 Hz), 5.97 (2H, s), 6.21 (1H, t, J=6.1 Hz), 6.76 (1H, d, J=8.6 Hz), 6.82-6.86 (4H, m), 6.92 (1H, brs), 7.08 (1H, dd, J=8.7 Hz, 3.0 Hz), 7.17 (2H, d, J=8.4 Hz), 7.24-7.32 (5H, m), 7.51 (1H, d, J=3.0 Hz).

The following compounds were produced in the same manner as in Example 2150.

TABLE 344

Example No. R₁₀₀₆ R₁₀₀₇ R₁₀₀₈ Xb₄₂ M ¹H NMR (solvent) δ ppm 2151 4-CF₃Ph— —CH₃ piperonyl —N(C₂H₅)— 1 (CDCl₃) 1.15 (3H, t, J = 7.1 Hz), 2.11 (3H, s), 2.30-2.50 (4H, m), 3.39 (2H, q, J = 7.1 Hz), 3.42 (2H, s), 3.42-3.55 (2H, m), 3.56-3.70 (2H, m), 3.80-4.05 (1H, m), 3.99 (2H, s), 4.36 (2H, s), 5.94 (2H, s), 6.44- 6.55 (2H, m), 6.58-6.64 (1H, m), 6.69- 6.78 (2H, m), 6.80-6.89 (2H, m), 6.94 (1 H, dd, J = 8.8 Hz, 3.1 Hz), 7.46 (2H, d, J = 8.0 Hz), 7.55- 7.63 (3H, m). 2152 3,4-Cl₂Ph— —CH₃ piperonyl —N(C₂H₅)— 1 (CDCl₃) 1.15 (3H, t, J = 7.1 Hz), 2.11 (3H, s), 2.32-2.49 (4H, m), 3.39 (2H, q, J = 7.1 Hz), 3.42 (2H, s), 3.44-3.55 (2H, m), 3.56-3.69 (2H, m), 3.79-3.94 (1H, m), 3.99 (2H, s), 4.15- 4.30 (2H, m), 5.94 (2H, s), 6.50 (1H, dd, J = 8.5 Hz, 3.0 Hz), 6.54 (1H, d, J = 3.0 Hz), 6.58-6.65 (1H, m), 6.69- 6.78 (2H, m), 6.82-6.88 (2H, m), 6.92 (1H, dd, J = 8.8 Hz, 3.0 Hz), 7.18 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.40 (1H, d, J = 8.2 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.57 (1H, d, J = 3.0 Hz). 2153 4-CF₃Ph— —H benzyl none 2 (DMSO-d₆) 2.28 (4H, brs), 2.54- 2.60 (2H, m), 2.73-2.79 (2H, m), 3.42- 3.46 (6H, m), 4.37 (2H, d, J = 5.9 Hz), 6.41 (1H, t, J = 6.1 Hz), 6.77 (1H, d, J = 8.7 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.08 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.17 (2H, d, J = 8.6 Hz), 7.22- 7.35 (5H, m), 7.50 (1H, d, J = 3.0 Hz), 7.58 (2H, d, J = 7.9 Hz), 7.69 (2H, d, J = 7.9 Hz). 2154 4-ClPh— —H benzyl none 2 (DMSO-d₆) 2.28 (4H, t, J = 4.8 Hz), 2.57 (2H, t, J = 7.3 Hz), 2.76 (2H, t, J = 7.3 Hz), 3.38-3.46 (6H, m), 4.25 (2H, d, J = 6.1 Hz), 6.32 (1H, t, J = 6.1 Hz), 6.76 (1H, d, J = 8.6 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.07 (1H, dd, J = 8.7 Hz, 3.1 Hz), 7.17 (2H, d, J = 8.6 Hz), 7.24-7.32 (5H, m), 7.38 (4H, brs), 7.50 (1H, d, J = 3.1 Hz). 2155 3,4-F₂Ph— —H benzyl none 2 (DMSO-d₆) 2.26-2.28 (4H, m), 2.57- 2.60 (2H, m), 2.73-2.79 (2H, m), 3.37- 3.46 (6H, m), 4.25 (2H, d, J = 5.8 Hz), 6.32 (1H, t, J = 5.8 Hz), 6.77 (1H, d, J = 8.6 Hz), 6.84 (2H, d, J = 8.3 Hz), 7.08 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.22- 7.43 (8H, m), 7.50 (1H, d, J = 3.1 Hz).

TABLE 345

Example No. R₁₀₀₉ R₁₀₁₀ R₁₀₁₁ Xb₄₃ M mp (° C.) or ¹H NMR (solvent) δ ppm 2156 4-CF₃Ph— —CH₃ piperonyl —N(CH₃)— 1 ¹H NMR (CDCl₃) 2.12 (3H, s), 2.42 (4H, t, J = 5.0 Hz), 2.98 (3H, s), 3.41-3.55 (4H, m), 3.56- 3.67 (2H, m), 3.77-3.99 (1H, m), 4.04 (2H, s), 4.36 (2H, s), 5.94 (2H, s), 6.52 (1H, dd, J = 8.7 Hz, 3.0 Hz), 6.56 (1H, d, J = 3.0 Hz), 6.59-6.64 (1H, m), 6.69- 6.78 (2H, m), 6.85 (1H, s), 6.87 (1H, d, J = 8.7 Hz), 6.93 (1H, dd, J = 8.8 Hz, 3.0 Hz), 7.46 (2H, d, J = 8.0 Hz), 7.54-7.63 (3H, m). 2157 3,4-Cl₂Ph— —CH₃ piperonyl —N(CH₃)— 1 mp 132-134 2158 4-CF₃Ph— —CH₃ piperonyl —N(Ac)— 1 ¹H NMR (CDCl₃) 1.94 (3H, s), 2.09 (3H, s), 2.30-2.50 (4H, m), 3.29-3.51 (4H, m), 3.52-3.69 (2H, m), 3.92-4.17 (1H, m), 4.29- 4.51 (4H, m), 5.94 (2H, s), 6.69- 6.77 (2H, m), 6.78 (1H, d, J = 8.7 Hz), 6.81-6.86 (1H, m), 6.91 (1H, d, J = 8.5 Hz), 7.01 (1H, dd, J = 8.7 Hz, 3.1 Hz), 7.18 (1H, dd, J = 8.5 Hz, 2.5 Hz), 7.28 (1H, d, J = 2.5 Hz), 7.48 (2H, d, J = 8.1 Hz), 7.56-7.64 (3H, m). 2159 3,4-Cl₂Ph— —CH₃ piperonyl —N(Ac)— 1 ¹H NMR (CDCl₃) 1.95 (3H, s), 2.07 (3H, s), 2.30-2.51 (4H, m), 3.29-3.50 (4H, m), 3.51-3.71 (2H, m), 3.92-4.18 (1H, m), 4.29 (2H, s), 4.42 (2H, s), 5.94 (2H, s), 6.69- 6.78 (3H, m), 6.82-6.87 (1H, m), 6.91 (1H, d, J = 8.5 Hz), 7.00 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.14- 7.23 (2H, m), 7.26-7.31 (1H, m), 7.41 (1H, d, J = 8.2 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.57 (1H, d, J = 3.0 Hz). 2160 Ph— —H benzyl none 2 ¹H NMR (DMSO-d₆) 2.27 (4H, brs), 2.54-2.60 (2H, m), 2.73- 2.79 (2H, m), 3.40-3.46 (6H, m), 4.25 (2H, d, J = 5.9 Hz), 6.28 (1H, t, J = 5.9 Hz), 6.76 (1H, d, J = 8.7 Hz), 6.84 (2H, d, J = 8.4 Hz), 7.09 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.17 (2H, d, J = 8.7 Hz), 7.23-7.38 (10H, m), 7.52 (1H, d, J = 3.0 Hz). 2161 4-CF₃Ph— —OCH₃ piperonyl —N(CH₃)— 1 mp 102-103 2162 3,4-Cl₂Ph— —OCH₃ piperonyl —N(CH₃)— 1 mp 145-146 2163 4-CF₃Ph— —OCH₃ piperonyl —N(C₂H₅)— 1 mp 160.0-160.5 2164 3,4-Cl₂Ph— —OCH₃ piperonyl —N(C₂H₅)— 1 mp 133-134 2165 3,4-Cl₂Ph— —F piperonyl —N(CH₃)— 1 mp 134-137

TABLE 346

Example No. R₁₀₁₂ R₁₀₁₃ Xb₄₄ M mp (° C.) or ¹H NMR (CDCl₃) δ ppm 2166 4-CF₃Ph— —OCH₃ none 2 ¹H NMR 2.38-2.44 (4H, m), 2.56-2.67 (2H, m), 2.88-2.99 (2H, m), 3.31-3.45 (2H, m), 3.40 (2H, s), 3.57-3.69 (2H, m), 3.76 (3H, s), 3.80-4.06 (1H, m), 4.37 (2H, s), 5.94 (2H, s), 6.68-6.81 (4H, m), 6.83- 6.87 (2H, m), 6.96 (1H, d, J = 8.0 Hz), 6.98 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.46 (2H, d, J = 8.0 Hz), 7.54 (1H, d, J = 2.6 Hz), 7.59 (2H, d, J = 8.0 Hz). 2167 4-CF₃Ph— —F —N(C₂H₅)— 1 mp 106-107 2168 4-CF₃Ph— —F —N(CH₃)— 1 mp 163-164 2169 3,4-Cl₂Ph— —F —N(C₂H₅)— 1 mp 107.5-109.0 2170 4-CF₃Ph— —H —N(SO₂CH₃)— 1 ¹H NMR 2.41 (4H, brs), 3.18 (3H, s), 3.35 (2H, brs), 3.42 (2H, s), 3.62 (2H, brs), 4.14 (1H, brs), 4.41 (2H, brs), 4.50 (2H, s), 5.94 (2H, s), 6.70-6.76 (2H, m), 6.80- 6.83 (2H, m), 6.98-7.04 (3H, m), 7.47- 7.56 (4H, m), 7.60-7.63 (3H, m).

Example 2171 Production of 1-(4-benzylpiperazin-1-yl)-3-[(4-(5-dibenzylaminopyridin-2-yloxy)phenyl]propane-1-one

3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-benzylpiperazin-1-yl)propane-1-one (1.0 g, 2.4 mmol) was dissolved in DMF (30 mL). To this solution were added potassium carbonate (0.73 g, 5.28 mmol), sodium iodide (0.76 g, 5.04 mmol) and benzyl bromide (0.60 mL, 5.04 mmol), and the resulting solution was stirred at room temperature overnight. This reaction solution was concentrated under reduced pressure. The residue was diluted with chloroform, and washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform:methanol=80:1), to thereby yield 0.67 g of the title compound.

Appearance: Yellow oil

¹H NMR (DMSO-d₆) δ 2.27 (4H, brs), 2.50-2.59 (2H, m), 2.73-2.78 (2H, m), 3.37-3.45 (6H, m), 4.68 (4H, s), 6.78 (1H, d, J=8.9 Hz), 6.85 (2H, d, J=8.4 Hz), 7.17 (2H, d, J=8.6 Hz), 7.20-7.36 (16H, m), 7.54 (1H, d, J=3.1 Hz).

Example 2172 Production of 2-[(4-{5-[(3,4-dichlorobenzyl)ethylamino]pyridin-2-yloxy}phenyl)methylamino]-1-(4-piperonylpiperazin-1-yl)ethanone

2-({4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}methylamino)-1-(4-piperonylpiperazin-1-yl)ethanone (1.59 g, 2.5 mmol) was dissolved in dichloroethane (80 mL). To this solution were added acetoaldehyde (1.40 mL, 25.0 mmol) and sodium triacetyloxy borohydride (1.59 mL, 7.5 mmol) under ice cooling. To the resulting solution was added dropwise acetic acid (0.43 mL, 7.5 mmol), and this solution was stirred at room temperature for 16 hours. The resulting reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform:methanol=50:1). The obtained solid was recrystallized from ethanol, to thereby yield 0.65 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.17 (3H, t, J=7.1 Hz), 2.41 (4H, brs), 2.99 (3H, s), 3.36-3.44 (4H, m), 3.48 (2H, brs), 3.62 (2H, brs), 4.04 (2H, s), 4.35 (2H, s), 5.95 (2H, s), 6.67-6.77 (5H, m), 6.85 (1H, brs), 6.97 (2H, d, J=9.1 Hz), 7.01 (1H, dd, J=8.9 Hz, 3.1 Hz), 7.07 (1H, dd, J=8.2 Hz, 2.0 Hz), 7.32 (1H, d, J=2.0 Hz), 7.37 (1H, d, 8.3 Hz), 7.63 (1H, d, J=3.0 Hz); MS 661 (M⁺).

The following compounds were produced in the same manner as in Example 2172.

TABLE 347

Example No. R₁₀₁₄ R₁₀₁₅ R₁₀₁₆ Xb₄₅ M ¹H NMR (CDCl₃) δ ppm 2173 4-CF₃Ph— —H piperonyl —N(CH₃)— 1 2.44 (4H, brs), 2.99 (6H, s), 3.39- 3.62 (6H, m), 4.04 (2H, s), 4.48 (2H, s), 5.95 (2H, s), 6.62-6.78 (5H, m), 6.86 (1H, brs), 6.97 (2H, d, J = 9.1 Hz), 7.08 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.34 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 8.1 Hz), 7.69 (1H, d, J = 3.1 Hz). 2174 3,4-Cl₂Ph— —H piperonyl —N(CH₃)— 2 2.32-2.40 (4H, m), 2.53-2.58 (2H, m), 2.92 (3H, s), 2.97 (3H, s), 3.37- 3.40 (4H, m), 3.59-3.63 (2H, m), 3.66- 3.72 (2H, m), 4.37 (2H, s), 5.94 (2H, s), 6.66-6.76 (5H, m), 6.83 (1H, d, J = 1.0 Hz), 6.98 (2H, d, J = 9.1 Hz), 7.04-7.11 (2H, m), 7.32 (1H, d, J = 2.0 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.67 (1H, d, J = 3.1 Hz). 2175 4-CF₃Ph— —H piperonyl —N(CH₃)— 2 2.32-2.39 (4H, m), 2.52-2.57 (2H, m), 2.92 (3H, s), 2.99 (3H, s), 3.36- 3.40 (4H, m), 3.59-3.63 (2H, m), 3.66- 3.72 (2H, m), 4.48 (2H, s), 5.94 (2H, s), 6.67-6.76 (5H, m), 6.83 (1H, d, J = 1.0 Hz), 6.98 (2H, d, J = 9.2 Hz), 7.09 (1H, dd, J = 9.1 Hz, 3.1 Hz), 7.34 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 8.1 Hz), 7.68 (1H, d, J = 2.8 Hz). 2176 3,4-Cl₂Ph— —H piperonyl —N(CH₃)— 1 2.40-2.44 (4H, m), 2.96 (3H, s), 3.00 (3H, s), 3.43 (2H, brs), 3.49 (2H, brs), 3.62 (2H, brs), 4.05 (2H, s), 4.36 (2H, s), 5.95 (2H, s), 6.67- 6.77 (5H, m), 6.85 (1H, brs), 6.97 (2H, d, J = 9.1 Hz), 7.06 (1H, dd, J = 8.3 Hz, 1.7 Hz), 7.07 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.32 (1H, d, J = 2.0 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.69 (1H, d, J = 3.1 Hz). 2177 4-CF₃Ph— —F benzyl none 0 2.46 (4H, brs), 3.02 (3H, s), 3.54 (6H, brs), 4.52 (2H, s), 6.89 (1H, d, J = 8.9 Hz), 7.14 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.17-7.21 (2H, m), 7.28-7.35 (8H, m), 7.58 (2H, d, J = 8.1 Hz), 7.62 (1H, d, J = 2.8 Hz). 2178 3,4-Cl₂Ph— —F benzyl none 0 2.47 (4H, brs), 3.00 (3H, s), 3.55- 3.73 (6H, m), 4.40 (2H, s), 6.89 (1H, d, J = 8.9 Hz), 7.06 (1H, dd, J = 8.2 Hz, 1.7 Hz), 7.14 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.17-7.22 (3H, m), 7.28-7.33 (6H, m), 7.39 (1H, d, J = 8.3 Hz), 7.61 (1H, d, J = 3.3 Hz).

TABLE 348

Example mp (° C.) or ¹H NMR No. R₁₀₁₇ R₁₀₁₈ R₁₀₁₉ Form (DMSO-d₆) δ ppm 2179 4-CF₃Ph— —CH₃ —C₂H₅ fumarate mp 157-159 dec 2180 3,4-Cl₂Ph— —CH₃ —C₂H₅ fumarate mp 148-151 dec 2181 4-CF₃Ph— —CH₃ —CH₃ fumarate mp 151-154 2182 3,4-Cl₂Ph— —CH₃ —CH₃ hydrochloride mp 139-142 2183 4-CF₃Ph— —CH₃ —Ac hydrochloride mp 199.5-201.5 2184 3,4-Cl₂Ph— —CH₃ —Ac hydrochloride mp 188.5-190.0 2185 4-CF₃Ph— —OCH₃ —CH₃ oxalate ¹H NMR 2.48-2.81 (4H, m), 2.93 (3H, s), 2.94 (3H, s), 3.36- 3.85 (9H, m), 4.25 (2H, s), 4.56 (2H, s), 6.0 (2H, s), 6.12 (1H, dd, J = 8.8 Hz, 2.8 Hz), 6.29 (1H, d, J = 2.8 Hz), 6.66 (1H, d, J = 9.0 Hz), 6.77 (1H, d, J = 8.8 Hz), 6.79-6.98 (3H, m), 7.22 (1H, dd, J = 9.0 Hz, 3.2 Hz), 7.42 (2H, d, J = 8.1 Hz), 7.52 (1H, d, J = 3.2 Hz), 7.67 (2H, d, J = 8.1 Hz). 2186 3,4-Cl₂Ph— —OCH₃ —CH₃ hydrochloride ¹H NMR 2.75-3.18 (8H, m), 3.21- 3.42 (2H, m), 3.63 (3H, s), 3.83- 4.52 (10H, m), 6.06 (2H, s), 6.16 (1H, dd, J = 8.8 Hz, 2.7 Hz), 6.34 (1H, d, J = 2.7 Hz), 6.68 (1H, d, J = 9.0 Hz), 6.79 (1H, d, J = 8.8 Hz), 6.94-7.06 (2H, m), 7.16- 7.24 (2H, m), 7.27 (1H, dd, J = 9.0 Hz, 3.2 Hz), 7.47 (1H, d, J = 2.0 Hz), 7.53 (1H, d, J = 3.2 Hz), 7.56 (1H, d, J = 8.2 Hz), 10.91- 11.26 (1H, m). 2187 4-CF₃Ph— —OCH₃ —C₂H₅ fumarate mp 159-162 2188 3,4-Cl₂Ph— —OCH₃ —C₂H₅ fumarate mp 154-157 2189 4-CF₃Ph— —F —CH₃ hydrobromide mp 211-212 2190 3,4-Cl₂Ph— —F —CH₃ hydrobromide mp 206.5-207.0 2191 4-CF₃Ph— —F —C₂H₅ hydrobromide mp 151.0-152.5 2192 3,4-Cl₂Ph— —F —C₂H₅ hydrobromide mp 172.5-174.5

TABLE 349

Example No. R₁₀₂₀ R₁₀₂₁ R₁₀₂₂ M Form ¹H NMR (DMSO-d₆) δ ppm 2193 Ph— —CH₃ —H 2 dihydro- 2.50-3.07 (10H, m), 3.22-3.31 (2H, m), chloride 3.45-3.50 (1H, m), 4.03-4.08 (1H, m), 4.30 (2H, d, J = 3.8 Hz), 4.42-4.55 (3H, m), 6.85-6.92 (3H, m), 7.19-7.26 (5H, m), 7.30-7.35 (3H, m), 7.45-7.47 (3H, m), 7.58-7.60 (2H, m), 7.66 (1H, d, J = 2.8 Hz), 11.33 (2H, brs). 2194 3,4-Cl₂Ph— —CH₃ —H 0 dihydro- 2.50-2.51 (2H, m), 3.03 (3H, s), 3.13- chloride 3.48 (6H, m), 4.34-4.37 (2H, m), 4.58 (2H, s), 6.97 (1H, d, J = 8.9 Hz), 7.04 (2H, d, J = 8.4 Hz), 7.23 (1H, dd, J = 8.4 Hz, 1.5 Hz), 7.34 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.44-7.47 (5H, m), 7.51 (1H, d, J = 1.5 Hz), 7.58-7.61 (3H, m), 7.70 (1H, d, J = 3.3 Hz), 11.52 (2H, brs). 2195 4-CF₃Ph— —CH₃ —H 0 dihydro- 3.06 (3H, s), 3.00-3.20 (2H, m), 3.20- chloride 3.40 (2H, m), 3.45 (2H, brs), 4.20- 4.50 (2H, m), 4.34 (2H, s), 4.69 (2H, s), 6.97 (1H, d, J = 8.9 Hz), 7.04 (2H, d, J = 8.8 Hz), 7.33 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.41-7.49 (7H, m), 7.55-7.68 (2H, m), 7.70 (1H, d, J = 3.1 Hz), 7.71 (2H, d, J = 8.0 Hz). 2196 3,4-Cl₂Ph— —CH₃ —H 2 dihydro- 2.49-3.07 (10H, m), 3.23-3.27 (2H, m), chloride 3.45-3.55 (1H, m), 4.03-4.08 (1H, m), 4.30 (2H, d, J = 4.3 Hz), 4.42-4.47 (1H, m), 4.54 (2H, s), 6.87 (1H, d, J = 9.1 Hz), 6.90 (2H, d, J = 8.6 Hz), 7.19-7.23 (3H, m), 7.32 (1H, dd, J = 8.9 Hz, 3.3 Hz), 7.45-7.50 (4H, m), 7.57-7.64 (4H, m), 11.33 (2H, brs). 2197 4-CF₃Ph— —C₂H₅ —F 0 hydro- 1.21 (3H, t, J = 6.9 Hz), 2.50-2.51 (2H, chloride m), 3.14-3.38 (6H, m), 3.49 (2H, q, J = 6.9 Hz), 4.34 (2H, brs), 4.61 (2H, brs), 6.98 (1H, d, J = 8.9 Hz), 7.25-7.29 (3H, m), 7.42-7.50 (7H, m), 7.58 (2H, brs), 7.69 (2H, d, J = 8.1 Hz), 11.12 (1H, brs). 2198 3,4-Cl₂Ph— —C₂H₅ —F 0 hydro- 1.10 (3H, t, J = 7.0 Hz), 2.49-2.52 (2H, chloride m), 3.13 (2H, brs), 3.32-3.58 (6H, m), 4.33 (2H, brs), 4.50 (2H, brs), 6.99 (1H, d, J = 9.1 Hz), 7.20-7.31 (4H, m), 7.42-7.57 (6H, m), 7.58-7.60 (3H, m), 11.14 (1H, brs).

TABLE 350

Example No. R₁₀₂₃ R₁₀₂₄ R₁₀₂₅ M Form mp (° C.) or ¹H NMR (solvent) δ ppm 2199 3,4-Cl₂Ph— —H —CH₃ 2 free ¹H NMR (CDCl₃) 1.17 (3H, t, J = 7.1 Hz), 2.32-2.39 (4H, m), 2.52- 2.57 (2H, m), 2.91 (3H, s), 3.36- 3.44 (6H, m), 3.59-3.63 (2H, m), 3.66-3.71 (2H, m), 4.35 (2H, s), 5.95 (2H, s), 6.67-6.76 (5H, m), 6.83 (1H, d, J = 1.0 Hz), 6.98 (2H, d, J = 9.1 Hz), 7.03 (1H, dd, J = 9.1 Hz, 3.3 Hz), 7.07 (1H, dd, J = 8.9 Hz, 2.1 Hz), 7.32 (1H, d, J = 2.0 Hz), 7.47 (1H, d, J = 8.3 Hz), 7.62 (1H, d, J = 3.1 Hz). 2200 4-CF₃Ph— —H —CH₃ 2 free ¹H NMR (CDCl₃) 1.19 (3H, t, J = 7.1 Hz), 2.32-2.38 (4H, m), 2.52- 2.57 (2H, m), 2.91 (3H, s), 3.36- 3.47 (6H, m), 3.59-3.63 (2H, m), 3.66-3.71 (2H, m), 4.47 (2H, s), 5.94 (2H, s), 6.67-6.76 (5H, m), 6.83 (1H, d, J = 1.0 Hz), 6.97 (2H, d, J = 9.2 Hz), 7.03 (1H, dd, J = 9.1 Hz, 3.1 Hz), 7.35 (2H, d, J = 7.9 Hz), 7.56 (2H, d, J = 7.9 Hz), 7.63 (1H, d, J = 2.8 Hz). 2201 3,4-Cl₂Ph— —CH₃ —CH₃ 1 hydrochloride mp 167-170 dec 2202 3,4-CF₃Ph— —CH₃ —Ac 1 hydrochloride mp 186-189 2203 3,4-Cl₂Ph— —CH₃ —Ac 1 hydrochloride mp 188.5-191.0 2204 4-CF₃Ph— —OCH₃ —CH₃ 1 oxalate ¹H NMR (DMSO-d₆) 1.08 (3H, t, J = 7.0 Hz), 2.50-2.81 (4H, m), 2.93 (3H, s), 3.41 (2H, q, J = 7.0 Hz), 3.33- 3.72 (7H, m), 3.77 (2H, s), 4.25 (2H, s), 4.52 (2H, s), 6.0 (2H, s), 6.12 (1H, dd, J = 8.8 Hz, 2.7 Hz), 6.28 (1H, d, J = 2.7 Hz), 6.64 (1H, d, J = 9.0 Hz), 6.76 (1H, d, J = 8.7 Hz), 6.80-6.94 (2H, m), 6.97 (1H, brs), 7.15 (1H, dd, J = 9.0 Hz, 3.2 Hz), 7.34-7.50 (3H, m), 7.66 (2H, d, J = 8.1 Hz). 2205 3,4-Cl₂Ph— —OCH₃ —CH₃ 1 hydrochloride ¹H NMR (DMSO-d₆) 1.06 (3H, t, J = 6.9 Hz), 2.75-3.16 (5H, m), 3.21- 3.48 (4H, m), 3.62 (3H, s), 3.71- 4.52 (10H, m), 6.06 (2H, s), 6.16 (1H, dd, J = 8.8 Hz, 2.7 Hz), 6.34 (1H, d, J = 2.7 Hz), 6.67 (1H, d, J = 8.9 Hz), 6.78 (1H, d, J = 8.8 Hz), 6.94-7.06 (2H, m), 7.13-7.28 (3H, m), 7.41- 7.52 (2H, m), 7.56 (1H, d, J = 8.3 Hz), 10.83-11.19 (1H, m).

TABLE 351

Example No. R₁₀₂₆ R₁₀₂₇ R₁₀₂₈ Form mp (° C.) 2206 4-CF₃Ph— —CH₃ —C₂H₅ oxalate 126-128 2207 3,4-Cl₂Ph— —CH₃ —C₂H₅ oxalate 111-113 2208 4-CF₃Ph— —CH₃ —C₂H₅ oxalate 120-123 2209 4-CF₃Ph— —OCH₃ —CH₃ hydrobromide 205-208 2210 3,4-Cl₂Ph— —OCH₃ —C₂H₅ hydrobromide 133-135 2211 4-CF₃Ph— —F —CH₃ hydrobromide 203-205 2212 3,4-Cl₂Ph— —F —CH₃ hydrobromide 185-188 2213 4-CF₃Ph— —F —C₂H₅ oxalate 121.0-122.5 2214 3,4-Cl₂Ph— —F —C₂H₅ hydrobromide 165.0-166.5

TABLE 352

Example No. R₁₀₂₉ R₁₀₃₀ ¹H NMR (CDCl₃) δ ppm 2215 —H

1.45 (9H, s), 2.39-2.43 (4H, m), 3.01 (3H, s), 3.41-3.44 (4H, m), 3.50 (2H, s), 4.41 (2H, s), 6.82 (1H, d, J = 8.9 Hz), 7.01 (2H, d, J = 8.4 Hz), 7.08-7.13 (2H, m), 7.27-7.41 (4H, m), 7.70 (1H, d, J = 8.6 Hz). 2216 —CH₃

2.20 (3H, s), 2.98 (3H, s), 3.06 (1H, dd, J = 14.0 Hz, 10.1 Hz), 3.52 (1H, dd, J = 14.0 Hz, 3.8 Hz), 4.38 (2H, s), 4.50 (1H, dd, J = 10.1 Hz, 3.8 Hz), 6.77 (1H, d, J = 8.9 Hz), 6.91 (1H, d, J = 8.3 Hz), 7.03 (1H, dd, J = 8.3 Hz, 2.1 Hz), 7.05-7.16 (3H, m), 7.32 (1H, d, J = 2.1 Hz), 7.39 (1H, d, J = 8.3 Hz), 7.67 (1H, d, J = 3.1 Hz).

TABLE 353

Example No. R₁₀₃₁ R₁₀₃₂ R₁₀₃₃ ¹H NMR (CDCl₃) δppm 2217 3,4-Cl₂Ph— —CH₃ —H 2.41 (4H, brs), 3.02 (3H, s), 3.19 (3H, s), 3.36 (2H, brs), 3.42 (2H, s), 3.60 (2H, brs), 4.41 (2H, s), 4.51 (2H, s), 5.95 (2H, s), 6.73-6.77 (2H, m), 6.84-6.87 (2H, m), 7.03 (2H, d, J = 8.9 Hz), 7.07 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.12 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.33 (1H, d, J = 2.0 Hz), 7.40 (1H, d, J = 8.3 Hz), 7.59 (2H, d, J = 8.9 Hz), 7.69 (1H, d, J = 3.1 Hz). 2218 3,4-Cl₂Ph— —C₂H₅ —H 1.21 (3H, t, J = 7.1 Hz), 2.41 (4H, brs), 3.18 (3H, s), 3.36 (2H, brs), 3.42 (2H, s), 3.46 (2H, q, J = 7.1 Hz), 3.60 (2H, brs), 4.40 (2H, s), 4.50 (2H, s), 5.94 (2H, s), 6.73-6.77 (2H, m), 6.81-6.84 (2H, m), 7.01-7.10 (4H, m), 7.33 (1H, d, J = 2.0 Hz), 7.39 (1H, d, J = 8.3 Hz), 7.54 (2H, d, J = 9.1 Hz), 7.64 (1H, d, J = 3.0 Hz). 2219 4-CF₃Ph— —CH₃ —H 2.41 (4H, brs), 3.05 (3H, s), 3.19 (3H, s), 3.34- 3.36 (2H, m), 3.42 (2H, s), 3.60 (2H, brs), 4.50 (2H, s), 4.54 (2H, s), 5.95 (2H, s), 6.73-6.74 (2H, m), 6.83 (1H, brs), 6.85 (1H, d, J = 8.9 Hz), 7.03 (2H, d, J = 8.9 Hz), 7.13 (1H, dd, J = 8.9 Hz, 3.3 Hz), 7.34 (2H, d, J = 7.9 Hz), 7.54 (2H, d, J = 8.9 Hz), 7.59 (2H, d, J = 8.1 Hz), 7.70 (1H, d, J = 3.1 Hz). 2220 4-CF₃Ph— —C₂H₅ —H 1.22 (3H, t, J = 7.1 Hz), 2.41 (4H, brs), 3.19 (3H, s), 3.35 (2H, brs), 3.42 (2H, s), 3.48 (2H, q, J = 7.1 Hz), 3.60 (2H, brs), 4.50 (2H, s), 4.52 (2H, s), 5.95 (2H, s), 6.70-6.77 (2H, m), 6.82 (1H, d, J = 8.7 Hz), 6.84 (1H, brs), 7.02 (2H, d, J = 8.9 Hz), 7.07 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.36 (2H, d, J = 7.9 Hz), 7.54 (2H, d, J = 8.9 Hz), 7.58 (2H, d, J = 8.1 Hz), 7.65 (1H, d, J = 3.0 Hz). 2221 3,4-Cl₂Ph— —CH₃ —CH₃ 2.21 (3H, s), 2.42 (4H, brs), 3.00 (3H, s), 3.21 (3H, s), 3.34-3.38 (2H, m), 3.42 (2H, s), 3.59-3.62 (2H, m), 4.39 (2H, s), 4.51 (2H, s), 5.95 (2H, s), 6.73- 6.77 (2H, m), 6.80-6.83 (2H, m), 6.91 (1H, d, J = 8.6 Hz), 7.06 (1H, dd, J = 8.2 Hz, 2.1 Hz), 7.12 (1 H, dd, J = 8.9 Hz, 3.1 Hz), 7.32-7.44 (4H, m), 7.65 (1H, d, J = 3.1 Hz). 2222 4-CF₃Ph— —CH₃ —CH₃ 2.21 (3H, s), 2.42 (4H, brs), 3.02 (3H, s), 3.20 (3H, s), 3.34-3.38 (2H, m), 3.42 (2H, s), 3.58-3.62 (2H, m), 4.51 (4H, brs), 5.94 (2H, s), 6.70-6.76 (2H, m), 6.79-6.83 (2H, m), 6.90 (1H, d, J = 8.6 Hz), 7.12 (1H, dd, J = 8.9 Hz, 3.3 Hz), 7.32-7.39 (3H, m), 7.43 (1H, d, J = 2.5 Hz), 7.58 (2H, d, J = 8.1 Hz), 7.66 (1H, d, J = 3.0 Hz).

TABLE 354

Example No. R₁₀₃₄ R₁₀₃₅ R₁₀₃₆ ¹H NMR (CDCl₃) δ ppm 2223 3,4-Cl₂Ph— —C₂H₅ —CH₃ 1.19 (3H, t, J = 7.1 Hz), 2.21 (3H, s), 2.41 (4H, brs), 3.20 (3H, s), 3.34-3.37 (2H, m), 3.42 (2H, s), 3.43 (2H, q, J = 7.1 Hz), 3.58-3.62 (2H, m), 4.38 (2H, s), 4.50 (2H, s), 5.95 (2H, s), 6.70- 6.77 (2H, m), 6.79 (1H, d, J = 8.9 Hz), 6.83 (1H, d, J = 0.8 Hz), 6.91 (1H, d, J = 8.6 Hz), 7.04-7.09 (2H, m), 7.32-7.43 (4H, m), 7.60 (1H, d, J = 3.0 Hz). 2224 4-CF₃Ph— —C₂H₅ —CH₃ 1.21 (3H, t, J = 7.1 Hz), 2.21 (3H, s), 2.41 (4H, brs), 3.20 (3H, s), 3.34-3.37 (2H, m), 3.42 (2H, s), 3.46 (2H, q, J = 7.1 Hz), 3.58-3.62 (2H, m), 4.50 (4H, brs), 5.94 (2H, s), 6.70-6.74 (2H, m), 6.78 (1H, d, J = 9.2 Hz), 6.83 (1H, brs), 6.90 (1H, d, J = 8.6 Hz), 7.04-7.08 (1H, m), 7.34-7.43 (4H, m), 7.57 (2H, d, J = 8.1 Hz), 7.60 (1H, d, J = 3.0 Hz). 2225 4-CF₃Ph— —CH₃ —OCH₃ 2.42 (4H, brs), 3.01 (3H, s), 3.21 (3H, s), 3.37 (2H, brs), 3.42 (2H, s), 3.61 (2H, brs), 3.78 (3H, s), 4.27 (2H, s), 4.53 (2H, s), 5.94 (2H, s), 6.72- 6.76 (2H, m), 6.84 (2H, d, J = 8.4 Hz), 7.00 (1H, d, J = 8.4 Hz), 7.10-7.16 (2H, m), 7.24-7.26 (1H, m), 7.33 (2H, d, J = 8.1 Hz), 7.57 (2H, d, J = 7.9 Hz), 7.62 (1H, d, J = 3.0 Hz). 2226 4-CF₃Ph— —C₂H₅ —OCH₃ 1.20 (3H, t, J = 6.9 Hz), 2.42 (4H, brs), 3.21 (3H, s), 3.36 (2H, brs), 3.40-3.43 (4H, m), 3.61 (2H, brs), 3.77 (3H, s), 4.48 (2H, s), 4.52 (2H, s), 5.94 (2H, s), 6.73-6.76 (2H, m), 6.81-6.85 (2H, m), 6.99 (1H, d, J = 8.6 Hz), 7.07 (1H, dd, J = 9.1 Hz, 3.3 Hz), 7.14 (1H, dd, J = 8.4 Hz, 2.3 Hz), 7.24 (1H, d, J = 2.5 Hz), 7.34 (2H, d, J = 8.1 Hz), 7.54-7.57 (3H, m).

TABLE 355

Example No. R₁₀₃₇ R₁₀₃₈ R₁₀₃₉ ¹H NMR (solvent) δ ppm 2227 3,4-Cl₂Ph— —CH₃ —H (CDCl₃) 2.20 (3H, s), 2.48-2.54 (4H, m), 2.97 (3H, s), 3.44 (2H, s), 3.70-3.73 (2H, m), 4.23-4.27 (2H, m), 4.37 (2H, s), 5.95 (2H, s), 6.73-6.77 (3H, m), 6.85 (1H, brs), 6.95 (1H, d, J = 8.6 Hz), 7.06 (1lH, dd, J = 8.2 Hz, 2.0 Hz), 7.10 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.32 (1H, d, J = 2.0 Hz), 7.37 (1H, dd, J = 8.6 Hz, 2.6 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 2.5 Hz), 7.66 (1H, d, J = 2.8 Hz), 9.12 (1H, brs). 2228 4-CF₃Ph— —CH₃ —H (CDCl₃) 2.20 (3H, s), 2.48-2.54 (4H, m), 3.00 (3H, s), 3.44 (2H, s), 3.72 (2H, t, J = 5.0 Hz), 4.23-4.27 (2H, m), 4.49 (2H, s), 5.95 (2H, s), 6.73-6.77 (3H, m), 6.85 (1H, brs), 6.95 (1H, d, J = 8.7 Hz), 7.10 (1H, dd, J = 8.9 Hz, 3.3 Hz), 7.32-7.39 (3H, m), 7.52 (1H, d, J = 2.5 Hz), 7.57 (2H, d, J = 8.1 Hz), 7.67 (1H, d, J = 3.3 Hz), 9.12 (1H, brs). 2229 3,4-Cl₂Ph— —C₂H₅ —H (CDCl₃) 1.18 (3H, t, J = 7.1 Hz), 2.20 (3H, s), 2.48- 2.53 (4H, m), 3.41 (2H, q, J = 7.1 Hz), 3.44 (2H, s), 3.70-3.73 (2H, m), 4.23-4.27 (2H, m), 4.36 (2H, s), 5.95 (2H, s), 6.72-6.77 (3H, m), 6.85 (1H, brs), 6.95 (1H, d, J = 8.6 Hz), 7.02-7.09 (2H, m), 7.32- 7.39 (3H, m), 7.51 (1H, d, J = 2.6 Hz), 7.60 (1H, d, J = 3.1 Hz), 9.12 (1H, brs). 2230 4-CF₃Ph— —C₂H₅ —H (CDCl₃) 1.19 (3H, t, J = 7.1 Hz), 2.20 (3H, s), 2.48- 2.53 (4H, m), 3.43 (2H, q, J = 7.1 Hz), 3.44 (2H, s), 3.70-3.73 (2H, m), 4.23-4.27 (2H, m), 4.48 (2H, s), 5.95 (2H, s), 6.71-6.77 (3H, m), 6.85 (1H, brs), 6.95 (1H, d, J = 8.7 Hz), 7.04 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.32-7.38 (3H, m), 7.51 (1H, d, J = 2.5 Hz), 7.56 (2H, d, J = 8.1 Hz), 7.61 (1H, d, J = 3.1 Hz). 9.11 (1H, brs). 2231 3,4-Cl₂Ph— —C₂H₅ —CH₃ a mixture of the rotational isomers (DMSO-d₆) 1.09 (3H, t, J = 6.93 Hz), 2.29-2.42 (7H, m), 3.22-3.54 (11H, m), 4.48 (2H, s), 5.97-5.99 (2H, m), 6.64-6.94 (5H, m), 7.07-7.27 (4H, m), 7.46- 7.59 (3H, m). 2232 4-CF₃Ph— —C₂H₅ —CH₃ a mixture of the rotational isomers (DMSO-d₆) 1.12 (3H, t, J = 6.93 Hz), 2.07-2.42 (7H, m), 3.22-3.55 (11H, m), 4.59 (2H, s), 5.97-5.99 (2H, m), 6.65-6.94 (5H, m), 7.07-7.18 (1H, m), 7.23- 7.29 (2H, m), 7.44 (2H, d, J = 8.08 Hz), 7.53 (1H, d, J = 3.13 Hz), 7.67 (2H, d, J = 8.41 Hz).

TABLE 356

Example No. R₁₀₄₀ ¹H NMR (DMSO-d₆) δ ppm 2233 3,4-Cl₂Ph— a mixture of the rotational isomers 2.09-2.12 (3H, m), 2.66-4.53 (18H, m), 6.05-6.08 (2H, m), 6.88- 6.93 (2H, m), 6.96-7.11 (3H, m), 7.19-7.25 (3H, m), 7.32-7.36 (1H, 7.48 (1H, d, J = 2.1 Hz), 7.55-7.60 (2H, m), 11.35 (1H, brs). 2234 4-CF₃Ph— a mixture of the rotational isomers 2.10-2.12 (3H, m), 2.66-4.64 (18H, m), 6.05-6.08 (2H, m), 6.87- 6.92 (2H, m), 6.96-7.11 (3H, m), 7.18-7.25 (2H, m), 7.30-7.35 (1H, m), 7.43 (2H, d, J = 8.1 Hz), 7.60-7.61 (1H, m), 7.68 (2H, d, J = 8.2 Hz), 11.27 (1H, brs).

Example 2235 Production of (4-{5-[benzyl-(3,4-dichlorobenzyl)amino]pyridin-2-yloxy}(4-benzylpiperazin-1-yl)methanone

(4-benzylpiperazin-1-yl){4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}methanone (1.09 g, 2.0 mmol) was dissolved in DMF (30 mL). To this solution were added potassium carbonate (0.28 g, 2.0 mmol) and benzyl bromide (0.24 mL, 2.0 mmol), and the resulting solution was stirred at room temperature for 2 hours, then subsequently stirred for 1 hour at 70° C. To the resulting solution were further added potassium carbonate (0.03 g, 0.2 mmol) and benzyl bromide (0.02 mL, 0.2 mmol), and this solution was stirred for 3 hours at 70° C. To the resulting solution were again added potassium carbonate (0.03 g, 0.2 mmol), benzyl bromide (0.02 mL, 0.2 mmol) and sodium iodide (0.15 g, 1.0 mmol), and this solution was stirred for overnight at 70° C. The resulting reaction solution was concentrated under reduced pressure. The residue was diluted with chloroform, and this solution was washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (ethyl acetate), to thereby yield 0.64 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 2.37 (4H, brs), 3.28-3.50 (6H, m), 4.71 (2H, s), 4.73 (2H, s), 6.90 (1H, d, J=8.9 Hz), 6.99 (2H, d, J=8.6 Hz), 7.22-7.37 (14H, m), 7.52 (1H, d, J=2.0 Hz), 7.58-7.61 (2H, m).

The following compounds were produced in the same manner as in Example 2235.

TABLE 357

Example No. R₁₀₄₁ R₁₀₄₂ R₁₀₄₃ ¹H NMR (CDCl₃) δppm 2236 3,4-Cl₂PhCON(CH₃)— —OCH₃ —C₂H₅ 1.19 (3H, t, J = 7.1 Hz), 2.42 (4H, t, J = 4.8 Hz), 3.30-3.55 (4H, m), 3.43 (2H, s), 3.44 (3H, s), 3.58-3.70 (2H, m), 3.67 (3H, s), 4.03 (2H, s), 5.95 (2H, s), 6.19 (1H, dd, J = 8.8 Hz, 2.8 Hz), 6.30 (1H, d, J = 2.8 Hz), 6.70-6.75 (2H, m), 6.79 (1H, d, J = 8.9 Hz), 6.85 (1H, s), 6.92 (1H, d, J = 8.8 Hz), 7.05 (1H, dd, J = 8.1 Hz, 2.0 Hz), 7.27 (1H, d, J = 8.1 Hz), 7.35 (1H, dd, J = 8.9 Hz, 2.6 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.80 (1H, d, J = 2.6 Hz). 2237 4-CF₃PhCON(CH₃)— —CH₃ —CH₃ 1.97 (3H, s), 2.43 (4H, t, J = 5.0 Hz), 3.00 (3H, s), 3.44 (2H, s), 3.47 (3H, s), 3.42- 3.57 (2H, m), 3.63 (2H, brs), 4.06 (2H, s), 5.95 (2H, s), 6.44-6.55 (2H, m), 6.67- 6.79 (3H, m), 6.82-6.90 (2H, m), 7.40- 7.47 (1H, m), 7.37 (2H, d, J = 8.1 Hz), 7.48 (2H, d, J = 8.1 Hz), 7.81 (1H, brs). 2238 4-CF₃PhCON(CH₃)— —OCH₃ —C₂H₅ 1.18 (3H, t, J = 7.1 Hz), 2.41 (4H, t, J = 4.9 Hz), 3.40 (2H, q, J = 7.1 Hz), 3.42 (2H, t, J = 3.5 Hz), 3.47 (3H, s), 3.42-3.59 (2H, m), 3.63 (5H, s), 4.02 (2H, s), 5.95 (2H, s), 6.18 (1H, dd, J = 8.7 Hz, 2.8 Hz), 6.28 (1H, d, J = 2.8 Hz), 6.69-6.78 (2H, m), 6.77 (1H, d, J = 8.8 Hz), 6.85 (1H, s), 6.90 (1H, d, J = 8.7 Hz), 7.35 (1H, d, J = 8.8 Hz), 7.38 (2H, d, J = 8.4 Hz), 7.48 (2H, d, J = 8.4 Hz), 7.79 (1H, brs). 2239 3,4-Cl₂PhN(CH₃)CO— —OCH₃ —C₂H₅ 1.18 (3H, t, J = 7.1 Hz), 2.42 (4H, t, J = 5.0 Hz), 3.42 (2H, s), 3.43 (2H, q, J = 7.1 Hz), 3.45 (3H, s), 3.55 (2H, brs), 3.65 (5H, brs), 4.02 (2H, s), 5.95 (2H, s), 6.19 (1H, dd, J = 8.7 Hz, 2.8 Hz), 6.29 (1H, d, J = 2.8 Hz), 6.71-6.74 (3H, m), 6.85 (1H, brs), 6.87 (1H, dd, J = 8.6 Hz, 2.5 Hz), 6.92 (1H, d, J = 8.7 Hz), 7.20 (1H, d, J = 2.5 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.64 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.05 (1H, d, J = 1.8 Hz). 2240 3,4-Cl₂PhSO₂N(CH₃)— —F —CH₃ 2.44 (2H, brs), 3.03 (3H, s), 3.19 (3H, s), 3.44 (2H, brs), 3.47 (2H, brs), 3.62 (2H, brs), 4.08 (2H, brs), 4.08 (2H, s), 5.95 (2H, s), 6.41 (1H, dd, J = 8.2 Hz, 3.1 Hz), 6.42- 6.50 (1H, m), 6.70-6.79 (2H, m), 6.85 (1H, brs), 6.90 (1H, d, J = 8.7 Hz), 7.04 (1H, t, J = 7.8 Hz), 7.34 (1H, dd, J = 8.4 Hz, 2.2 Hz), 7.50 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.72 (1H, d, J = 2.2 Hz), 7.77 1H, d, J = 2.8 Hz).

TABLE 358

Example No. R₁₀₄₄ R₁₀₄₅ Xb₄₆ Form mp (° C.) or ¹H NMR 2241 4-CH₃PhCON(CH₃)— —CH₃ —N(SO₂CH₃)— free ¹H NMR (CDCl₃) δ 2.05 (3H, s), 2.42 (4H, brs), 3.20 (3H, s), 3.34-3.37 (2H, m), 3.42 (2H, s), 3.48 (3H s), 3.59-3.61 (2H, m), 4.52 (2H, s), 5.95 (2H, s), 6.70-6.77 (2H, m), 6.84 (1H, brs), 6.86 (1H, d, J = 8.7 Hz), 6.97 (1H, d, J = 8.1 Hz), 7.37-7.51 (7H, m), 7.79 (1H, brs). 2242 3,4-Cl₂PhCON(CH₃)— —CH₃ —N(SO₂CH₃)— free ¹H NMR (CDCl₃) δ 2.09 (3H, s), 2.42 (4H, brs), 3.21 (3H, s), 3.37 (2H, brs), 3.43 (2H, s), 3.46 (3H, s), 3.61 (2H, brs), 4.52 (2H, s), 5.95 (2H, s), 6.70-6.80 (2H, m), 6.84 (1H, brs), 6.89 (1H, d, J = 8.7 Hz), 6.99 (1H, d, J = 8.4 Hz), 7.09 (1H, dd, J = 8.2 Hz, 1.8 Hz), 7.29 (1H, d, J = 8.2 Hz), 7.38 (1H, d, J = 2.0 Hz), 7.42-7.46 (3H, m), 7.80 (1H, d, J = 2.5 Hz). 2243

—H —CH₂— free mp 133.0-134.0 2244

—H —CH₂— free mp 117.0-118.0 2245 4-CF₃PhN(CH₃)SO₂— —H —CH₂— free ¹H NMR (CDCl₃) δ 2.33- 2.41 (4H, m), 2.63 (2H, t, J = 7.3 Hz), 2.99 (2H, t, J = 7.3 Hz), 3.22 (3H, s), 3.40 (4H, brs), 3.61- 3.64 (2H, m), 5.93 (2H, s), 6.69-6.76 (2H, m), 6.84 (1H, s), 6.94 (1H, d, J = 8.7 Hz), 7.06 (2H, d, J = 8.6 Hz), 7.27-7.31 (4H, m), 7.59 (2H, d, J = 8.4 Hz), 7.71 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.37 (1H, d, J = 2.6 Hz). 2246 F₃CCH═CHCON(CH₃)— —CH₃ —N(CH₃)— hydro- mp 161.0-164.0 chloride

TABLE 359

Example No. R₁₀₄₆ ¹H NMR (solvent) δppm 2247 3,4-Cl₂PhCON(CH₃)— a mixture of the rotational isomers (DMSO-d₆) 1.93 (3H, brs), 2.08-2.42 (4H, m), 3.21- 3.56 (12H, m), 5.97-5.99 (2H, m), 6.66-6.89 (3H, m), 6.90-7.07 (2H, m), 7.13-7.32 (3H, m), 7.48-7.54 (2H, m), 7.85-7.89 (2H, m). 2248 4-CF₃PhCON(CH₃)— a mixture of the rotational isomers (DMSO-d₆) 1.87 (3H, brs), 2.07-2.41 (4H, m), 3.20- 3.55 (12H, m), 5.97-5.99 (2H, m), 6.66-6.89 (3H, m), 6.98-7.04 (2H, m), 7.12-7.21 (1H, m), 7.24-7.30 (1H, m), 7.47 (2H, brs), 7.61-7.64 (2H, m), 7.86-7.89 (2H, m). 2249 3,4-Cl₂PhSO₂N(CH₃)— (CDCl₃) 2.17 (3H, s), 2.23-2.53 (4H, m), 3.21(3H, brs), 3.32-3.82 (9H, m), 5.93-5.95 (2H, m), 6.65-6.78 (3H, m), 6.85-6.95 (1H, m), 7.02-7.06 (1H, m), 7.07- 7.18 (2H, m), 7.38-7.42 (1H, m), 7.53-7.58 (2H, m), 7.67-7.68 (1H, m), 7.78-7.80 (1H, m). 2250 4-CF₃PhSO₂N(CH₃)— a mixture of the rotational isomers (DMSO-d₆) 2.07-2.43 (7H, m), 3.16-3.56 (12H, m), 6.67-6.70 (2H, m), 6.76-6.89 (3H, m), 7.05-7.36 (4H, m), 7.61-7.66 (1H, m), 7.77-7.80 (2H, m), 7.91-7.80 (3H, m). 2251 4-CF₃PhSO₂N(C₂H₅)— (CDCl₃) 1.13 (3H, t, J = 7.1 Hz), 2.18 (3H, s), 2.23-2.52 (4H, m), 3.32-3.66 (11H, m), 5.93-5.95 (2H, m), 6.66- 6.95 (4H, m), 7.04-7.19 (3H, m), 7.46 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.73-7.80 (5H, m).

TABLE 360

Example No. R₁₀₄₇ R₁₀₄₈ R₁₀₄₉ ¹H NMR (CDCl₃) δppm 2252 4-CF₃Ph— —H benzyl 1.34-1.46 (2H, m), 1.85-2.03 (3H, m), 2.29 (2H, d J = 6.8 Hz), 2.43 (4H, brs), 2.73 (2H, t, J = 12.0 Hz), 3.19 (3H, s), 3.47-3.65 (8H, m), 6.83 (1H, d, J = 8.7 Hz), 6.92-7.03 (4H, m), 7.26-7.33 (5H, m), 7.48 (1H, dd, J = 8.9 Hz, 2.8 Hz), 7.70-7.78 (5H, m). 2253 3,4-Cl₂Ph— —H piperonyl 1.33-1.46 (2H, m), 1.85-2.04 (3H, m), 2.29 (2H, d, J = 6.8 Hz), 2.39-2.42 (4H, m), 2.74 (2H, t, J = 12.2 Hz), 3.19 (3H, s), 3.43 (2H, s), 3.46-3.64 (6H, m), 5.94 (2H, s), 6.70-6.77 (2H, m), 6.83 (2H, d, J = 8.9 Hz), 6.92-7.03 (4H, m), 7.38 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.49 (1H, dd, J = 8.9 Hz, 2.8 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.70 (1H, d, J = 2.1 Hz), 7.81 (1H, d, J = 2.3 Hz). 2254 4-CF₃Ph— —H piperonyl 1.34-1.46 (2H, m), 1.85-2.02 (3H, m), 2.28 (2H, d, J = 6.8 Hz), 2.39-2.42 (4H, m), 2.74 (2H, t, J = 12.0 Hz), 3.20 (3H, s), 3.43 (2H, s), 3.46-3.64 (6H, m), 5.94 (2H, s), 6.70-6.77 (2H, m), 6.81-7.03 (6H, m), 7.49 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.71- 7.78 (5H, m). 2255 4-CF₃Ph— —OCH₃ benzyl 1.31-1.42 (2H, m), 1.86-2.00 (3H, m), 2.29 (2H, d, J = 6.8 Hz), 2.42-2.45 (4H, m), 2.76 (2H, t, J = 12.0 Hz), 3.19 (3H, s), 3.49-3.69 (8H, m), 3.75 (3H, s), 6.51 (1H, dd, J = 8.7 Hz, 2.5 Hz), 6.59 (1H, d, J = 2.5 Hz), 6.83 (1H, d, J = 8.7 Hz), 6.98 (1H, d, J = 8.7 Hz), 7.26-7.33 (5H, m), 7.47 (1H, dd, J = 8.9 Hz, 2.8 Hz), 7.69-7.75 (5H, m). 2256 3,4-Cl₂Ph— —H benzyl 1.39-1.42 (2H, m), 1.84-2.02 (3H, m), 2.28 (2H, d, J = 6.8 Hz), 2.41-2.45 (4H, m), 2.73 (2H, t, J = 12.2 Hz), 3.19 (3H, s), 3.48-3.95 (8H, m), 6.83 (1H, d, J = 8.7 Hz), 6.92-7.03 (4H, m), 7.27-7.39 (6H, m), 7.48 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.70 (1H, d, J = 2.1 Hz), 7.81 (1H, d, J = 2.3 Hz). 2257 3,4-Cl₂Ph— —OCH₃ benzyl 1.34-1.42 (2H, m), 1.82-2.00 (3H, m), 2.29 (2H, d, J = 6.8 Hz), 2.41-2.45 (4H, m), 2.76 (2H, t, J = 12.2 Hz), 3.19 (3H, s), 3.49-3.65 (8H, m), 3.75 (3H, s), 6.51 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.58 (1H, d, J = 2.6 Hz), 6.84 (1H, d, J = 8.7 Hz), 6.98 (1H, d, J = 8.6 Hz), 7.26-7.39 (6H, m), 7.46 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.69 (1H, d, J = 2.0 Hz), 7.78 (1H, d, J = 2.5 Hz).

TABLE 361

Example No. R₁₀₅₀ R₁₀₅₁ ¹H NMR (CDCl₃) δppm 2258 4-CF₃PhN(CH₃)SO₂— —H 1.34-1.46 (2H, m), 1.85-2.00 (3H, m), 2.28 (2H, d, J = 6.8 Hz), 2.39-2.43 (4H, m), 2.75 (2H, t, J = 12.2 Hz), 3.21 (3H, s), 3.43 (2H, s), 3.46-3.64 (6H, m), 5.94 (2H, s), 6.70-6.77 (2H, m), 6.85-7.02 (6H, m), 7.26-7.31 (2H, m), 7.59 (2H, d, J = 8.6 Hz), 7.67 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.39 (1H, d, J = 2.1 Hz). 2259 4-CF₃PhSO₂N(C₂H₅)— —OCH₃ 1.11 (3H, t, J = 7.1 Hz), 1.30-1.42 (2H, m), 1.85- 2.00 (3H, m), 2.29 (2H, d, J = 6.8 Hz), 2.39-2.44 (4H, m), 2.76 (2H, t, J = 12.2 Hz), 3.40-3.70 (10H, m), 3.75 (3H, s), 5.94 (2H, s), 6.51 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.59 (1H, d, J = 2.6 Hz), 6.74-6.87 (4H, m), 6.99 (1H, d, J = 8.7 Hz), 7.37-7.48 (2H, m), 7.54 (1H, d, J = 8.4 Hz), 7.73-7.75 (2H, m). 2260 4-CF₃PhSO₂N(C₂H₅)— —H 1.11 (3H, t, J = 7.1 Hz), 1.35-1.47 (2H, m), 1.85- 2.00 (3H, m), 2.29 (2H, d, J = 6.8 Hz), 2.40-2.42 (4H, m), 2.74 (2H, t, J = 12.0 Hz), 3.42-3.48 (4H, m), 3.57-3.64 (6H, m), 5.94 (2H, s), 6.74-6.77 (2H, m), 6.82-7.04 (6H, m), 7.41 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.72-7.94 (5H, m). 2261 4-CF₃PhSO₂N(CH₃)— —OCH₃ 1.39-1.47 (2H, m), 1.86-2.00 (3H, m), 2.29 (2H, d, J = 6.8 Hz), 2.41 (4H, brs), 2.76 (2H, t, J = 12.0 Hz), 3.19 (3H, s), 3.43 (2H, s), 3.48 (2H, brs), 3.60 (4H, brs), 3.64 (3H, s), 5.93 (2H, s), 6.51 (1H, dd, J = 8.7 Hz, 2.5 Hz), 6.59 (1H, d, J = 2.5 Hz), 6.74-6.84 (4H, m), 6.98 (1H, d, J = 8.6 Hz), 7.46 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.69-7.76 (5H, m). 2262 4-CF₃PhN(CH₃)SO₂— —CH₃ 1.34-1.45 (2H, m), 1.85-2.01 (3H, m), 2.07 (3H, s), 2.29 (2H, d, J = 6.8 Hz), 2.41-2.43 (4H, m), 2.73 (2H, t, J = 12.0 Hz), 3.22 (3H, s), 3.43 (2H, s), 3.46- 3.77 (6H, m), 5.94 (2H, s), 6.74-6.94 (7H, m), 7.29 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.4 Hz), 7.68 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.38 (1H, d, J = 2.5 Hz). 2263 3,4-Cl₂PhSO₂N(CH₃)— —CH₃ 1.38-1.41 (2H, m), 1.84-1.98 (3H, m), 2.11 (3H, s), 2.29 (2H, d, J = 6.8 Hz), 2.41 (4H, brs), 2.72 (2H, t, J = 12.0 Hz), 3.19(3H, s), 3.43-3.64 (8H, m), 5.94 (2H, s), 6.74-6.85 (6H, m), 6.93 (1H, d, J = 8.6 Hz), 7.39 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.49 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.56(1H, d, J = 8.4 Hz), 7.67 (1H, d, J = 2.0 Hz), 7.78 (1H, d, J = 2.3 Hz). 2264 3,4-Cl₂PhSO₂N(CH₃)— —OCH₃ 1.39-1.47 (2H, m), 1.85-2.02 (3H, m), 2.29 (2H, d, J = 6.8 Hz), 2.39-2.44 (4H, m), 2.76 (2H, t, J = 12.2 Hz), 3.19 (3H, s), 3.43 (2H, s), 3.49 (2H, brs), 3.59- 3.73 (4H, m), 3.75 (3H, s), 5.94 (2H, s), 6.51 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.59 (1H, d, J = 2.6 Hz), 6.74- 6.85 (4H, m), 6.98 (1H, d, J = 8.6 Hz), 7.38 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.46 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.69 (1H, d, J = 2.1 Hz), 7.78 (1H, d, J = 2.8 Hz).

TABLE 362

Example No. Xb₄₇ R₁₀₅₂ ¹H NMR (CDCl₃) δppm 2265 —CO—

2.33 (2H, d, J = 5.1 Hz), 2.38 (2H, d, J = 5.1 Hz), 2.60 (2H, t, J = 5.1 Hz), 2.96 (2H, t, J = 8.0 Hz), 3.33-3.46 (2H, m), 3.40 (2H, s), 3.47 (3H, s), 3.62 (2H, t, J = 2.0 Hz), 5.94 (2H, s), 6.67- 6.79 (2H, m), 6.83 (1H, d, J = 8.7 Hz), 6.84 (1H, s), 6.99 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.34-7.45 (1H, m), 7.40 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.2 Hz), 7.85 (1 H, brs). 2266 —CO—

3.17 (3H, s), 3.21 (3H, s), 3.48 (3H, s), 6.70 (1H, d, J = 8.7 Hz), 6.72-6.84 (6H, m), 6.95 (1H, t, J = 7.4 Hz), 7.07 (2H, t, J = 7.8 Hz), 7.31-7.45 (3H, m), 7.46- 7.58 (2H, m), 7.79-7.92 (1H, m). 2267 —SO₂—

1.78-2.04 (4H, m), 2.11 (3H, s), 2.44 (4H, brs), 2.53-2.76 (3H, m), 3.19 (3H, s), 3.53 (4H, brs), 3.67 (4H, brs), 6.76- 6.81 (3H, m), 6.93 (1H, d, J = 8.6 Hz), 7.26-7.33 (5H, m), 7.49 (1H, dd, J = 8.9 Hz, 2.8 Hz), 7.70-7.79 (5H, m).

TABLE 363

Example No. R₁₀₅₃ Form ¹H NMR (DMSO-d₆) δppm 2268 —CH₃ free 2.39 (4H, brs), 3.32-3.51 (9H, m), 7.08 (1H, d, J = 8.7 Hz), 7.09 (2H, d, J = 8.4 Hz), 7.25-7.31 (6H, m), 7.41 (2H, d, J = 8.6 Hz), 7.55-7.58 (2H, m), 7.87 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.03 (1H, brs). 2269 benzyl hydro- 3.12-3.43 (8H, m), 4.33(2H, s), 5.09 (2H, s), 7.02 (1H, d, J = chloride 8.7 Hz), 7.07 (2H, d, J = 7.8 Hz), 7.26-7.33 (6H, m), 7.45- 7.48 (5H, m), 7.55-7.58 (3H, m), 7.67 (1H, brs), 7.77 (1H, d, J = 8.7 Hz), 7.85 (1H, brs), 11.09 (1H, brs).

Example 2270 Production of 1-(t-butoxycarbonyl)-4-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine

To a solution of N-[4-(4-bromophenoxy)phenyl]-3,4-dichlorobenzamide (4.94 g, 11.3 mmol) in THF (100 mL) was stirred at −85° C., and added a solution of 2.46 M n-butyl lithium hexane (9.65 mL, 23.7 mmol) dropwise over 10 minutes. Upon stirring for 20 minutes at the same temperature, crystals were precipitated. To this reaction solution was added a solution of 1-(t-butoxycarbonyl)-4-piperidone (2.48 g, 12.4 mmol) in THF (20 mL). The temperature of the solution was raised over 3 hours to −40° C., and then aqueous saturated ammonium chloride was added to the solution. The resulting reaction solution was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3 to 1:1), to yield 2.30 g of a white powder. These crystals were washed with ether, to thereby yield 1.80 g of the title compound.

Appearance: White powder

Melting point: 208-209° C.

Example 2271 Production of 1-(t-butoxycarbonyl)-4-(4-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-1,2,5,6-tetrahydropyridine

To a solution of 1-(t-butoxycarbonyl)-4-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine (1.56 g, 2.80 mmol) in toluene (32 mL) was added p-toluenesulfonic acid hydrate (53 mg, 0.28 mmol), and the resulting solution was refluxed for 18 hours. The resulting reaction solution was purified by silica gel column chromatography (dichloromethane:methanol=20:1), to thereby yield 1.35 g of the title compound.

Appearance: White powder

Melting point: 173-174° C.

Example 2272 Production of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine

To a solution of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-(methoxymethoxy)piperidine (5.50 g, 11.0 mmol) in ethanol (110 mL) was added 2 M hydrochloric acid (55 mL, 110 mmol), and the resulting solution was stirred for 8 hours at 60° C. To the resulting reaction solution was added potassium carbonate (16 g) at room temperature, and the solvent was evaporated under reduced pressure. Water (200 mL) was added to the residue. Precipitated crystals were collected by filtration, to thereby yield 5.0 g of the title compound.

Appearance: Pale brown powder

Melting point: 178-180° C.

Example 2273 Production of 1-(3-{4-[(4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazine monohydrochloride

To a solution of 1-(t-butoxycarbonyl)-4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-propionyl)piperazine (2.40 g, 4.01 mmol) in dichloromethane (24 mL) was added trifluoroacetic acid (12 mL) under ice cooling, and the resulting solution was stirred for 3 hours at the same temperature. The solvent was evaporated. To the residue was added acetone (5 mL), and then added a saturated sodium bicarbonate solution to make the solution basic. The formed solids were collected by filtration and dried, whereby 2.00 g of a white powder free form was obtained. This free form (0.500 g) was dissolved in ethanol (10 mL) and 5 M hydrochloric acid (0.4 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from isopropanol, to thereby yield 0.388 g of the title compound.

Appearance: White powder

Melting point: 127-130° C.

The following compounds were produced in the same manner as in Example 2273.

TABLE 364

Example No. R₁₀₅₄ R₁₀₅₅ Form mp (° C.) or ¹H NMR (solvent) δppm 2274 —F

hydro- chloride mp 149-151 2275 —H

free mp 198-199 2276 —H

free mp 170-174 2277 —H

free ¹H NMR (CDCl₃) 2.43-2.46 (2H, m), 3.11 (2H, t, J = 5.5 Hz), 3.53 (2H, q, J = 3 Hz), 6.10 (1H, m), 6.97 (2H, d, J = 8.5 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.36 (2H, d, J = 8.5 Hz), 7.56-7.59 (3H, m), 7.68-7.69 (2H, m) 7.97 (1H, d, J = 2.0 Hz). 2278 —H

free ¹H NMR (DMSO-d₆) 1.32-1.36 (2H, m), 1.85-1.91 (2H, m), 2.32 (3H, s), 2.45 (1H, m), 2.66-2.71 (2H, m), 3.54-3.56 (2H, m), 4.13 (1H, m), 6.89-6.97 (6H, m), 7.65- 7.71 (3H, m), 7.82 (1H, d, J = 8.5 Hz), 7.93 (1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21 (1H, d, J = 2.0 Hz), 10.36 (1H, s). 2279 —H

free ¹H NMR (CDCl₃) 1.63 (2H, m), 1.83 (2H, brd, J = 14.0 Hz), 2.61 (1H, m), 2.75 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.20 (2H, brd, J = 12.0 Hz), 6.95 (2H, d, J = 8.5 Hz), 7.03 (2H, d, J = 9.0 Hz), 7.19 (2H, d, J = 8.5 Hz), 7.55 (1H, d, J = 8.0 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.69 (1H, dd, J = 8.0 Hz, 2.0 Hz), 7.69 (1H, brs), 7.97 (1H, d, J = 2.0 Hz).

TABLE 365

Example No. R₁₀₅₆ Xb₄₈ Xb₄₉ Form ¹H NMR (solvent) δppm 2280 3,4-Cl₂Ph— none —CO— trifluoro- (DMSO-d₆) 3.56 (2H, brs), 3.87 (2H, m), acetate 3.92(2H, brs), 7.14 (1H, d, J = 8.8 Hz), 7.20 (2H, dd, J = 6.7 Hz, 2.2 Hz), 7.35 (2H, dd, J = 6.7 Hz, 2.2 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.23 (1H, d, J = 2.1 Hz), 8.51 (1H, d, J = 2.7 Hz), 9.30 (2H, brs), 10.59 (1H, s). 2281 4-CF₃Ph— none —CH₂— free (CDCl₃) 3.07 (4H, t, J = 5.0 Hz), 3.15 (4H, t, J = 5.0 Hz), 6.92 (1H, d, J = 9.0 Hz), 6.96(2H, d, J = 9.0 Hz), 7.06 (2H, d, J = 9.0 Hz), 7.77 (1H, brs), 7.78 (2H, d, J = 8.0 Hz), 7.99 (2H, d, J = 8.0 Hz), 8.19 (1H, brd, J = 9.0 Hz), 8.25 (1H, d, J = 2.5 Hz). 2282 3,4-Cl₂Ph— none —CH₂— free (CDCl₃) 3.18 (4H, dd, J = 5.5 Hz, 2.5 Hz), 3.16 (4H, dd, J = 5.5 Hz, 2.5 Hz), 6.90 (1H, d, J = 9.0 Hz), 6.95 (2H, d, J = 9.0 Hz), 7.05 (2H, d, J = 9.0 Hz), 7.58 (1H, d, J = 8.5 Hz), 7.71 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.88 (1H, brs), 7.98 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 9.0 Hz, 2.5 Hz), 8.24 (1H, d, J = 2.5 Hz). 2283 3,4-Cl₂Ph— —CH₂— —CH₂— free (DMSO-d₆) 2.45-2.47 (4H, m), 2.88- 2.92 (4H, m), 3.49 (2H, s), 7.05- 7.09 (3H, m), 7.33 (2H, d, J = 8.6 Hz), 7.84 (1H, d, J = 8.6 Hz), 7.95-7.99 (1H, m), 8.18-8.25 (2H, m), 8.51 (1H, d, J = 2.6 Hz), 10.62 (1H, s). 2284 3,4-Cl₂Ph— —CO— —CH₂— free (DMSO-d₆) 2.69 (4H, brs), 3.40 (4H, brs), 7.12-7.17 (3H, m), 7.41-7.44 (2H, m), 7.84 (1H, d, J = 8.4 Hz), 7.96 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.21-8.26 (2H, m), 8.52 (1H, d, J = 2.7 Hz), 10.62 (1H, brs). 2285 4-CF₃Ph— —CH₂— —CH₂— free (DMSO-d₆) 2.44-2.46 (4H, m), 2.89- 2.92 (4H, m), 3.49 (2H, s), 4.79 (1H, brs), 7.06-7.09 (3H, m), 7.33 (2H, d, J = 8.6 Hz), 7.94 (2H, d, J = 8.1 Hz). 8.16- 8.25 (3H, m), 8.52 (1H, d, J = 2.7 Hz), 10.65 (1H, s). 2286 3,4-(CH₃)₂Ph— —CO— —CH₂— free (DMSO-d₆) 2.29 (3H, s), 2.30 (3H, s), 2.73 (4H, brs), 3.44 (4H, brs), 7.09- 7.16 (3H, m), 7.29 (1H, d, J = 7.9 Hz), 7.40-7.44 (2H, m), 7.69-7.72 (1H, m), 7.75 (1H, brs), 8.22-8.26 (1H, m), 8.53 (1H, d, J = 2.8 Hz), 10.31 (1H, s).

TABLE 366

Example No. R₁₀₅₇ Xb₅₀ M ¹H NMR (solvent) δppm 2287 3,4-Cl₂PhCH₂N(CH₃)— none 1 (DMSO-d₆) 2.51-2.54 (4H, m), 3.00 (3H, s), 3.06-3.08 (4H, m), 3.50 (2H, s), 4.55 (2H, s), 6.88 (1H, d, J = 8.9 Hz), 6.94 (2H, d, J = 8.4 Hz), 7.19-7.32 (4H, m), 7.49 (1H, d, J = 1.5 Hz), 7.58 (1H, d, J = 8.2 Hz), 7.64 (1H, d, J = 3.1 Hz), 8.73 (1H, brs). 2288 4-CF₃PhCONH— none 3 (CDCl₃) 1.77-1.96 (6H, m), 2.35-2.44 (6H, m), 2.61-2.66 (2H, m), 6.92 (1H, d, J = 8.6 Hz), 7.01-7.05 (2H, m), 7.17-7.23 (2H, m), 7.74 (2H, d, J = 8.4 Hz), 8.00 (2H, d, J = 8.4 Hz), 8.21 (1H, dd, J = 8.6 Hz, 2.6 Hz), 8.27- 8.28 (2H, m). 2289 3,4-Cl₂PhCONH— —CO— 2 (DMSO-d₆) 2.59-2.69 (6H, m), 2.79- 2.85 (2H, m), 3.37-3.43 (4H, m), 4.31 (1H, brs), 7.00-7.06 (3H, m), 7.27 (2H, d, J = 8.6 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.16-8.22 (2H, m), 8.46 (1H, d, J = 2.3 Hz), 10.54 (1H, s). 2290 4-CF₃PhCONH— —COCO— 1 (CDCl₃) 1.69 (1H, brs), 2.51 (2H, t, J = 5.1 Hz), 2.77 (2H, t, J = 5.1 Hz), 3.15 (2H, t, J = 5.1 Hz), 3.53 (2H, t, 5.1 Hz), 4.05 (2H, s), 6.98 (1H, d, J = 8.7 Hz), 7.11 (2H, d, J = 8.5 Hz), 7.29 (2H, d, J = 8.5 Hz), 7.76 (2H, d, J = 8.2 Hz), 7.99 (2H, d, J = 8.2 Hz), 8.01 (1H, brs), 8.21 (1H, dd, J = 8.7 Hz, 2.7 Hz), 8.25 (1H, d, J = 2.7 Hz).

Example 2291 [3-(4-{5-[3-(3,4-Dichlorophenyl)ureido]pyridin-2-yloxy}-3-methylphenyl)-2-oxotetrahydropyrimidin-1-yl]acetic acid

¹H NMR (DMSO-d₆) δ 1.87-2.15 (5H, m), 3.25-3.47 (2H, m), 3.58-3.75 (2H, m), 3.95 (2H, s), 6.82-7.00 (2H, m), 7.01-7.12 (1H, m), 7.17 (1H, d, J=2.4 Hz), 7.29-7.32 (1H, m), 7.50 (1H, d, J=8.8 Hz), 7.85 (1H, d, J=2.4 Hz), 7.89-8.02 (1H, m), 8.11 (1H, d, J=2.7 Hz), 8.95 (1H, s), 9.17 (1H, s), 12.50 (1H, s).

The following compounds were produced in the same manner as in Reference Example 922.

TABLE 367

Example No. R₁₀₅₈ R₁₀₅₉ ¹H NMR (DMSO-d₆) δppm 2292 3,4-Cl₂Ph—

1.40-1.65 (2H, m), 1.95-2.18 (2H, m), 2.40- 2.65 (3H, m), 3.00 (2H, brs), 3.25 (1H, brs), 3.85 (1H, brs), 4.40 (1H, brs), 7.15 (1H, d, J = 9.0 Hz), 7.19 (2H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.7 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.99 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.22-8.30 (2H, m), 8.56 (1H, d, J = 2.0 Hz), 10.71 (1H, s). 2293 3,4-Cl₂Ph—

1.70-2.05 (4H, m), 2.60-2.80 (1H, m), 2.80- 3.05 (2H, m), 3.44 (2H, d, J = 7.1 Hz), 7.03 (1H, d, J = 8.7 Hz), 7.07 (2H, d, J = 8.9 Hz), 7.65 (2H, d, J = 8.9 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.98 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.20 (1H, dd, J = 8.7 Hz, 2.7 Hz), 8.26 (1H, d, J = 2.0 Hz), 8.50 (1H, d, J = 2.7 Hz), 10.22 (1H, s), 10.65 (1H, s). 2294 4-CF₃Ph—

1.75-1.90 (2H, m), 1.95-2.30 (2H, m), 2.84 (3H, s), 2.70-3.15 (2H, m), 3.20-3.42 (2H, m), 4.55 (1H, brs), 6.51 (1H, brs), 7.16 (1H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.47 (2H, d, J = 8.4 Hz), 7.94 (2H, d, J = 8.1 Hz), 8.22 (2H, d, J = 8.1 Hz). 8.31 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.60 (1H, d, J = 2.6 Hz), 10.84 (1H, s).

TABLE 368

Example No. R₁₀₆₀ R₁₀₆₁ Xb₅₁ M Form ¹H NMR (solvent) δppm 2295 —H —H none 0 dihydro- (DMSO-d₆) 3.16 (4H, brs), 3.75 (4H, chloride brs), 7.16 (1H, d, J = 8.9 Hz), 7.19 (2H, d, J = 8.7 Hz), 7.53 (2H, d, J = 8.7 Hz), 7.93 (2H, d, J = 8.1 Hz), 8.21 (2H, d, J = 8.1 Hz), 8.30 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.60 (1H, d, J = 2.5 Hz), 10.81 (1H, s). 2296 —H —H none 2 dihydro- (DMSO-d₆) 2.68 (1H, d, J = 6.5 Hz), chloride 2.71 (1H, d, J = 8.4 Hz), 2.82 (1H, d, J = 8.4 Hz), 2.84 (1H, d, J = 6.5 Hz), 3.04 (4H, brs), 3.70 (4H, t, J = 5.0 Hz), 7.03 (2H, d, J = 8.6 Hz), 7.05 (1H, d, J = 8.9 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.41 (1H, brs), 7.92 (2H, d, J = 8.5 Hz), 8.21 (2H, d, J = 8.5 Hz), 8.25 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.54 (1H, d, J = 2.8 Hz), 10.80 (1H, s). 2297 —CH₃ —H —N(CH₃)— 1 free (CDCl₃) 2.11 (3H, s), 2.74-2.96 (4H, m), 3.01 (3H, s), 3.39-3.70 (4H, m), 4.08 (2H, s), 6.54 (1H, dd, J = 8.6 Hz, 3.0 Hz), 6.57 (1H, d, J = 3.0 Hz), 6.81 (1H, d, J = 8.9 Hz), 6.91 (1H, d, J = 8.6 Hz), 7.75 (2H, d, J = 8.2 Hz), 7.93-8.02 (3H, m), 8.13 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.24 (1H, d, J = 2.7 Hz). 2298 —H —CH₂CONHNH₂ none 0 trihydro- (DMSO-d₆) 3.42 (4H, brs), 3.75 (4H, chloride brs), 4.21 (2H, s), 7.17 (1H, d, J = 8.8 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.94 (2H, d, J = 8.1 Hz), 8.22 (2H, d, J = 8.1 Hz), 8.31 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.62 (1H, d, J = 2.6 Hz), 10.87 (1H, s).

Example 2299 Production of 1-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)-4-piperonylpiperazine monohydrochloride

To a suspension consisting of 1-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazine (0.500 g, 1.00 mmol) and diisopropylethylamine (0.262 mL, 1.50 mmol) in acetonitrile (12 mL) was added piperonyl chloride (0.188 g, 1.10 mmol), and the resulting solution was heated to reflux for 1.5 hours. Water was added to this reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), to thereby yield 0.486 g of a free form. This free form was dissolved in ethanol (10 mL) and 5 M hydrochloric acid (0.3 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from 90% ethanol (17.5 mL), to thereby yield 0.322 g of the title compound.

Appearance: White powder

Melting point: 221-224° C.

A crude titled product (9.95 g, 14.9 mmol) obtained using the same procedures was recrystallized from 80% ethanol (350 mL), to thereby yield 9.37 g of the title compound.

Appearance: White powder

Melting point: 232-234

The following compounds were produced in the same manner as in Example 2299.

TABLE 369

Example No. R₁₀₆₂ Xb₅₂ Xb₅₃ R₁₀₆₃ Form mp (° C.) or ¹H NMR (CDCl₃) δppm 2300 —H —(CH₂)₂— —CO— —(CH₂)₂Ph hydro- mp 205-207 chloride 2301 —H —(CH₂)₂— —CO— —(CH₂)₂OH hydro- mp 101-105 chloride 2302 —H —(CH₂)₂— —CO— —(CH₂)₃Ph ½ mp 156-159 fumarate 2303 —F —(CH₂)₂— —CO— 4-CH₃PhCH₂— free mp 105-107 2304 —F —(CH₂)₂— —CO— 4-CH₃OPhCH₂— free mp 137-139 2305 —F —(CH₂)₂— —CO— 2-CF₃PhCH₂— free mp 130-132 2306 —F —(CH₂)₂— —CO— 2-naphthyl- hydro- mp 172-175 methyl chloride 2307 —H —(CH₂)₂— —CO— —CH₂COOC₂H₅ free ¹H NMR 1.25 (3H, t, J = 7.1 Hz), 2.39-2.53 (4H, m), 2.58 (2H, t, J = 7.8 Hz), 2.90 (2H. t, J = 7.8 Hz), 3.19 (2H, s), 3.36-3.48 (2H, m), 3.58-3.69 (2H, m), 4.16 (2H, q, J = 7.1 Hz), 6.89 (2H, d, J = 8.6 Hz), 6.96 (2H, d, J = 8.9 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.47-7.59 (3H, m), 7.69 (1H, dd, J = 8.3 Hz, 2.1 Hz), 7.96 (1H, d, J = 2.1 Hz), 8.14 (1H, brs). 2308 —H none —CO— —(CH₂)₂Ph hydro- mp 210-218 chloride 2309 —H none none —(CH₂)₂Ph free mp 214-215 2310 —H none none benzyl free mp 189-190 2311 —H none none —(CH₂)₃Cl free ¹H NMR 2.00 (2H, m), 2.56 (2H, t, J = 7.0 Hz), 2.62-2.64 (4H, m), 3.16-3.18 (4H, m), 3.64 (2H, t, J = 7.0 Hz), 6.92 (2H, d, J = 7.0 Hz), 6.95-6.98 (4H, m), 7.52 (2H, d, J = 9.0 Hz), 7.57 (1H, d, J = 8.0 Hz), 7.69 (1H, dd, J = 8.0 Hz, 2.0 Hz), 7.70 (1H, s), 7.96 (1H, d, J = 2.0 Hz). 2312 —H none none —CH₂COOC₂H₅ free ¹H NMR 1.30 (3H, t, J = 7.0 Hz), 2.76 (4H, t, J = 5.0 Hz), 3.21 (4H, t, J = 5.0 Hz), 3.28 (2H, s), 4.21 (2H, q, J = 7.0 Hz), 6.91-6.98 (6H, m), 7.52 (2H, d, J = 9.0 Hz), 7.57 (1H, d, J =8.5 Hz), 7.69 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.72 (1H, brs), 7.96 (1H, d, J = 2.0 Hz).

TABLE 370

Example No. R₁₀₆₄ mp (° C.) or ¹H NMR (CDCl₃) δppm 2313

mp 189-195 2314

¹H NMR 2.60 (2H, brs), 2.85 (2H, m), 3.31 (2H, m), 3.39 (2H, s), 3.76 (3H, s), 6.00 (1H, brs), 6.95 (2H, d, J = 8.5 Hz), 7.03 (2H, d, J = 8.5 Hz), 7.34 (2H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.57 (1H, brs), 7.70 (1H, d, J = 7.0 Hz), 7.75 (1H, brs), 7.97 (1H, s). 2315

¹H NMR 1.28 (3H, t. J = 7.0 Hz), 1.60-1.70 (2H, m), 1.93-1.96 (2H, m), 2.46 (3H, s), 2.60-2.72 (3H, m), 3.37 (2H, s), 3.64-3.66 (2H, m), 4.20 (2H, q, J = 7.0 Hz), 6.93-6.98 (6H, m), 7.52 (2H, m), 7.57 (1H, d, J = 8.5 Hz), 7.68-7.70 (2H, m), 7.96 (1H, d, J = 2.0 Hz). 2316

¹H NMR 1.29 (3H, t, J = 7.0 Hz), 1.81-1.88 (4H, m), 2.30 (2H, brt, J = 11.0 Hz), 2.49 (1H, m), 3.06 (2H, brd, J = 11.0 Hz), 4.21 (2H, q, J = 7.0 Hz), 6.94 (2H, d, J = 8.5 Hz), 7.01 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 8.5 Hz), 7.55-7.68 (3H, m), 7.69 (1H, d, J = 2.0 Hz), 7.75 (1H, brs), 7.97 (1H, d, J = 2.0 Hz). 2317

¹H NMR 2.04 (2H, m), 2.56 (2H, brs), 2.62 (2H, t, J = 7.0 Hz), 2.72 (2H, t, J = 5.5 Hz), 3.17 (2H, brs), 3.64 (2H, t, J = 6.5 Hz), 6.02 (1H, brs), 6.96 (2H, d, J = 9.0 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.36 (2H, d, J = 9.0 Hz), 7.58 (3H, m), 7.70 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.77 (1H, brs), 7.98 (1H, d, J = 2.0 Hz).

TABLE 371

Example No. R₁₀₆₅ R₁₀₆₆ ¹H NMR (solvent) δppm 2318 4-CF₃Ph— —(CH₂)₂Ph (DMSO-d₆) 2.31-2.60 (6H, m), 2.67-2.81 (2H, m), 3.51 (4H, brs), 7.16 (1H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.5 Hz), 7.10-7.33 (5H, m), 7.44 (2H, d, J = 8.5 Hz), 7.94 (2H, d, J = 8.2 Hz), 8.17 (2H, d, J = 8.2 Hz), 8.26 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.55 (1H, d, J = 2.6 Hz), 10.67 (1H, s). 2319 3,4-Cl₂Ph— 4-CNPhCH₂— (CDCl₃) 2.46 (4H, brs), 3.59 (2H, s), 3.75 (4H, brs), 6.97 (1H, d, J = 8.9 Hz), 7.11-7.14 (2H, m), 7.40-7.43 (2H, m), 7.46 (2H, d, J = 7.8 Hz), 7.56-7.65 (3H, m), 7.72-7.76 (1H, m), 8.02 (1H, d, J = 2.2 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.27 (1H, brs), 8.30 (1H, d, J = 2.7 Hz). 2320 3,4-Cl₂Ph— —(CH₂)₂COPh (CDCl₃) 2.65 (4H, brs), 3.60-3.82 (4H, m), 3.89 (2H, s), 6.99 (1H, d, J = 8.7 Hz), 7.15 (2H, d, J = 8.6 Hz), 7.43-7.50 (4H, m), 7.56-7.60 (2H, m), 7.72-7.76 (1H, m), 7.97-8.02 (3H, m), 8.13- 8.21 (2H, m), 8.30 (1H, d, J = 2.5 Hz). 2321 3,4-Cl₂Ph— 3,4-(CH₃)₂PhCH₂— (CDCl₃) 2.25 (3H, s), 2.26 (3H, s), 2.44 (4H, brs), 3.47 (2H, s), 3.73 (4H, brs), 6.89 (1H, d, J = 8.9 Hz), 7.01-7.10 (5H, m), 7.32-7.36 (2H, m), 7.51 (1H, d, J = 8.4 Hz), 7.74-7.78 (1H, m), 8.05 (1H, d, J = 8.1 Hz), 8.09 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 9.06 (1H, brs). 2322 3,4-Cl₂Ph— 4-C(CH₃)₃COPhCH₂— (CDCl₃) 1.36 (9H, s), 2.48 (4H, brs), 3.58 (2H, s), 3.70 (4H, brs), 6.96 (1H, d, J = 8.7 Hz), 7.11- 7.14 (2H, m), 7.39-7.43 (4H, m), 7.57 (1H, d, J = 8.4 Hz), 7.69 (2H, d, J = 8.3 Hz), 7.73-7.77 (1H, m), 8.03 (1H, d, J = 2.0 Hz), 8.15 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 8.37 (1H, brs). 2323 3,4-Cl₂Ph— 4-PhCH₂OPhCH₂— (CDCl₃) 2.45 (4H, brs), 3.49 (2H, s), 3.73 (4H, brs), 5.06 (2H, s), 6.92-6.98 (3H, m), 7.11- 7.15 (2H, m), 7.23 (2H, d, J = 8.6 Hz), 7.32- 7.46 (7H, m), 7.57 (1H, d, J = 8.1 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.03 (1H, d, J = 2.2 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.26 (1H, brs), 8.29 (1H, d, J = 2.7 Hz). 2324 3,4-Cl₂Ph— 4-C(CH₃)₃PhCH₂— (CDCl₃) 1.32 (9H, s), 2.48 (4H, brs), 3.53 (2H, s), 3.70 (4H, brs), 6.98 (1H, d, J = 8.4 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.21-7.27 (2H, m), 7.36 (2H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.1 Hz), 7.72-7.76 (1H, m), 8.02 (1H, d, J = 2.2 Hz), 8.13 (1H, brs), 8.16-8.20 (1H, m), 8.30 (1H, d, J = 2.2 Hz). 2325 3,4-Cl₂Ph— 3-CH₃PhCH₂— (CDCl₃) 2.36 (3H, s), 2.47 (4H, brs), 3.52 (2H, s), 3.74 (4H, brs), 6.97 (1H, d, J = 8.7 Hz), 7.08- 7.26 (6H, m), 7.41-7.44 (2H, m), 7.58 (1H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.04 (1H, d, J = 2.1 Hz), 8.14-8.19 (1H, m), 8.26 (1H, brs), 8.30 (1H, d, J = 2.2 Hz).

TABLE 372

Example No. R₁₀₆₇ R₁₀₆₈ ¹H NMR (CDCl₃) δ ppm 2326 3,4-Cl₂Ph— 4-CH(CH₃)₂PhCH₂— 1.25 (6H, d, J = 7.3 Hz), 2.46 (4H, brs), 2.85- 2.96 (1H, m), 3.52 (2H, s), 3.75 (4H, brs), 6.95 (1H, d, J = 8.9 Hz), 7.10-7.13 (2H, m), 7.17- 7.26 (4H, m), 7.38-7.42 (2H, m), 7.57 (1H, d, J = 8.1 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.04 (1H, d, J = 2.2 Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 8.41 (1H, brs). 2327 3,4-Cl₂Ph— 4-CH₃PhCH₂— 2.34 (3H, s), 2.45 (4H, brs), 3.51 (2H, s), 3.73 (4H, brs), 6.93 (1H, d, J = 8.7 Hz), 7.07-7.22 (6H, m), 7.35-7.38 (2H, m), 7.54 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.05 (1H, d, J = 2.2 Hz), 8.12 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.30 (1H d, J = 2.7 Hz) 8.82 (1H, s). 2328 3,4-Cl₂Ph— 3,4-F₂PhCH₂— 2.45 (4H, brs), 3.49-3.73 (6H, m), 6.96 (1H, d, J = 8.7 Hz), 7.01-7.23 (5H, m), 7.39-7.42 (2H, m), 7.56 (1H, d, J = 8.4 Hz), 7.76 (1H, dd, J =8.4 Hz 2.1 Hz), 8.03 (1H, d, J = 2.1 Hz), 8.17 (1H, dd, J = 8.7 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 8.50 (1H, s). 2329 3,4-Cl₂Ph— 4-CH₃OPhCH₂— 2.43 (4H, brs), 3.48 (2H, s), 3.73 (4H, brs), 3.81 (3H, s), 6.85-6.93 (3H, m), 7.06-7.10 (2H, m), 7.21-7.24 (2H, m), 7.34-7.37 (2H, m), 7.53 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.05 (1H, d, J = 2.1 Hz), 8.10 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz) 8.90 (1H, s). 2330 4-CF₃Ph— 4-CF₃PhCH₂— 2.48 (4H, brs), 3.60 (2H, s), 3.70 (4H, brs), 7.00 (1H, d, J = 8.9 Hz), 7.12-7.17 (2H, m), 7.41- 7.48 (4H, m), 7.60 (2H, d, J = 7.9 Hz), 7.77 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.14 (1H, brs), 8.19-8.24 (1H, m), 8.32 (1H, d, J = 2.3 Hz). 2331 4-CF₃Ph— 3,4-(CH₃)₂PhCH₂— 2.25 (3H, s), 2.26 (3H, s), 2.45 (4H, brs), 3.47 (2H, s), 3.40-3.90 (4H, m), 6.98 (1H, d, J = 8.7 Hz), 6.97-7.10 (3H, m), 7.13 (2H, d, J = 8.7 Hz), 7.42 (2H, d, J = 8.7 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.18 (1H, brs), 8.20 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.31 (1H, d, J = 2.5 Hz). 2332 4-CF₃Ph— 3-CH₃PHCH₂— 2.35 (3H, s), 2.46 (4H, brs), 3.35-3.90 (4H, m), 3.50 (2H, s), 6.98 (1H, d, J = 8.9 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.05-7.30 (4H, m), 7.41 (2H, d, J = 8.6 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.19 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.28 (1H, brs), 8.31 (1H, d, J = 2.6 Hz). 2333 4-CF₃Ph— 4-CH₃PhCH₂— 2.34 (3H, s), 2.44 (4H, brs), 3.50 (2H, s), 3.35- 3.85 (4H, m), 6.97 (1H, d, J = 8.9 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.20 (2H, d, J = 8.1 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.75 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.18 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.32(1H, d, J = 2.5 Hz), 8.38 (1H, s).

TABLE 373

Example No. R₁₀₆₉ R₁₀₇₀ ¹H NMR (CDCl₃) δ ppm 2334 3,4-Cl₂Ph— 3-CH₃OPhCH₂— 2.47 (4H, brs), 3.46-3.82 (6H, m), 3.86 (3H, s), 6.80-6.84 (1H, m), 6.88-6.92 (2H, m), 6.95 (1H, d, J = 8.8 Hz), 7.10-7.13 (2H, m), 7.23 (1H, d, J = 8.1 Hz), 7.38-7.41 (2H, m), 7.56 (1H, d, J = 8.3 Hz), 7.73-7.77 (1H, m), 8.04 (1H, d, J = 2.1 Hz), 8.12- 8.16 (1H, m), 8.29 (1H, d, J = 2.7 Hz), 8.44 (1H, brs). 2335 3,4-Cl₂Ph— 2-quinolylmethyl 2.58 (4H, brs), 3.58-3.76 (4H, m), 3.88 (2H, s), 6.94 (1H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.6 Hz), 7.51-7.57 (2H, m), 7.62 (1H, d, J = 8.4 Hz), 7.68-7.84 (3H, m), 8.04 (1H, d, J = 2.1 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.12-8.17 (2H, m), 8.29 (1H, d, J = 2.5 Hz), 8.65 (1H, brs). 2336 3,4-Cl₂Ph— 4-CF₃PhCH₂— 2.47 (4H, brs), 3.44-3.85 (6H, m), 6.98 (1H, d, J = 8.9 Hz), 7.11-7.16 (2H, m), 7.39-7.48 (4H, m), 7.56-7.61 (3H, m), 7.75 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.02 (1H, d, J = 2.1 Hz), 8.14-8.18 (1H, m), 8.24 (1H, brs), 8.30 (1H, d, J = 2.6 Hz). 2337 3,4-Cl₂Ph— 4-CF₃OPhCH₂— 2.46 (4H, brs), 3.46-3.84 (6H, m), 6.96 (1H, d, J = 8.9 Hz), 7.10-7.20 (4H, m), 7.34-7.41 (4H, m), 7.56 (1H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.03 (1H, d, J = 2.1 Hz), 8.11-8.16 (1H, m), 8.30 (1H, d, J = 2.5 Hz), 8.49 (1H, brs). 2338 3,4-Cl₂Ph— PhO(CH₂)₂— 2.60 (4H, brs), 2.85 (2H, t, J = 5.4 Hz), 3.53- 3.75 (4H, m), 4.12 (2H, t, J = 5.4 Hz), 6.88- 6.99 (4H, m), 7.06-7.13 (2H, m), 7.25-7.37 (4H, m), 7.51 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.05 (1H, d, J = 2.1 Hz), 8.07-8.12 (1H, m), 8.32 (1H, d, J = 2.6 Hz), 9.10 (1H, brs). 2339 4-CF₃Ph— 4-CNPhCH₂— 2.45 (4H, brs), 3.58 (2H, s), 3.63 (4H, brs), 6.98 (1H, d, J = 8.8 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.41 (2H, d, J = 8.7 Hz), 7.46 (2H, d, J = 8.1 Hz), 7.62 (2H, d, J = 8.1 Hz), 7.75 (2H, d, J = 8.1 Hz), 8.01 (2H, d, J = 8.1 Hz), 8.20 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.28 (1H, brs), 8.33 (1H, d, J = 2.6 Hz). 2340 4-CF₃Ph— 3,4-F₂PhCH₂— 2.44 (4H, brs), 3.48 (2H, s), 3.64 (4H, brs), 6.98 (1H, d, J = 8.9 Hz), 6.97-7.25 (3H, m), 7.12 (2H, d. J = 8.7 Hz), 7.41 (2H, d, J = 8.7 Hz), 7.75 (2H, d, J = 8.0 Hz), 8.01 (2H, d, J = 8.0 Hz), 8.19 (1H, dd, J = 8.9 Hz, 2.3 Hz), 8.30 (1H, brs), 8.32 (1H, d, J = 2.3 Hz). 2341 4-CF₃Ph— 4-CH₃OPhCH₂— 2.43 (4H, brs), 3.48 (2H, s), 3.60 (4H, brs), 3.80 (3H, s), 6.86 (2H, d, J = 8.7 Hz), 6.96 (1H, d, J = 8.7 Hz), 7.11 (2H, d, J = 8.7 Hz), 7.22 (2H, d, J = 8.7 Hz), 7.38 (2H, d, J = 8.7 Hz), 7.74 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.17 (1H, dd, J = 8.7 Hz, 2.4 Hz), 8.32 (1H, d, J = 2.4 Hz), 8.52 (1H, s).

TABLE 374

Example No. R₁₀₇₁ R₁₀₇₂ mp (° C.) or ¹H NMR (CDCl₃) δ ppm 2342 3,4-(CH₃)₂Ph— 4-CNPhCH₂— ¹H NMR 2.33 (6H, s), 2.45 (4H, brs), 3.58 (2H, s), 3.64 (4H, brs), 6.97 (1H, d, J = 8.7 Hz), 7.11-7.16 (2H, m), 7.24 (1H, d, J = 7.6 Hz), 7.41-7.47 (4H, m), 7.58-7.67 (4H, m), 7.94 (1H, brs), 8.24 (1H, dd, J = 8.7 Hz, 2.7 Hz), 8.31 (1H, d, J = 2.7 Hz). 2343 3,4-(CH₃)₂Ph— 3,4-F₂PhCH₂— ¹H NMR 2.34 (6H, s), 2.45 (4H, brs), 3.48 (2H, s), 3.65 (4H, brs), 6.98 (1H, d, J = 8.9 Hz), 7.03-7.23 (6H, m), 7.41-7.46 (2H, m), 7.59- 7.62 (1H, m), 7.67 (1H, d, J = 1.8 Hz), 7.95 (1H, brs), 8.26 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.31 (1H, d, J = 2.7 Hz). 2344 4-CF₃Ph— 3-CH₃OPhCH₂— mp 118-120 2345 4-CF₃Ph— 2-quinolylmethyl ¹H NMR 2.56 (4H, brs), 3.43-3.81 (4H, m), 3.87 (2H, s), 6.94 (1H, d, J = 8.9 Hz), 7.08- 7.13 (2H, m), 7.35-7.40 (2H, m), 7.51-7.57 (1H, m), 7.61 (1H, d, J = 8.4 Hz), 7.68-7.74 (3H, m), 7.81-7.84 (1H, m), 8.01-8.20 (5H, m), 8.33 (1H, d, J = 2.7 Hz), 8.94 (1H, s). 2346 4-CF₃Ph— PHO(CH₂)₂— mp 161-162 2347 4-CF₃Ph—

¹H NMR 2.48 (4H, brs), 3.55 (2H, brs), 3.66 (2H, s), 3.75 (2H, brs), 6.97 (1H, d, J = 8.7 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.32- 7.43 (1H, m), 7.41 (2H, d, J = 8.4 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.70-7.80 (1H, m), 7.75 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.10 (1H, s), 8.20 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.32 (1H, d, J = 2.6 Hz), 8.41 (1H, s).

TABLE 375

Example No. R₁₀₇₃ R₁₀₇₄ ¹H NMR (CDCl₃) δ ppm 2348 3,4-Cl₂Ph— 2,6-F₂PhCH₂— 2.42 (4H, brs), 2.54-2.60 (2H, m), 2.83-2.88 (2H, m), 3.38-3.42 (2H, m), 3.55-3.58 (2H, m), 3.69 (2H, s), 6.85-6.98 (5H, m), 7.12 (2H, d, J = 8.6 Hz), 7.19-7.31 (1H, m), 7.48 (1H, d, J = 8.4 Hz), 7.74 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.99 (1H, d, J = 2.1 Hz), 8.14-8.18 (1H, m), 8.30 (1H, d, J = 2.8 Hz), 9.19 (1H, brs). 2349 3,4-Cl₂Ph— 4-CF₃PhCH₂— 2.33-2.41 (4H, m), 2.59-2.65 (2H, m), 2.92- 2.97 (2H, m), 3.40-3.44 (2H, m), 3.55 (2H, s), 3.61-3.64 (2H, m), 6.93 (1H, d, J = 8.8 Hz), 7.02-7.06 (2H, m), 7.20 (2H, d, J = 8.6 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.54-7.60 (3H, m), 7.74 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.01 (1H, d, J = 2.2 Hz), 8.17-8.21 (1H, m), 8.28 (1H, d, J = 2.6 Hz), 8.44 (1H, brs). 2350 4-CF₃Ph—

2.28 (2H, t, J = 4.9 Hz), 2.43 (2H, t, J = 4.9 Hz), 2.61 (2H, t, J = 7.5 Hz), 2.96 (2H, t, J = 7.5 Hz), 3.30 (2H, t, J = 4.9 Hz), 3.59 (2H, s), 3.63 (2H, t, J = 4.9 Hz), 6.96 (1H, d, J = 8.3 Hz), 7.04 (2H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.5 Hz), 7.36 (1H, dd, J = 8.5 Hz, 1.5 Hz), 7.53 (1H, d, J = 8.4 Hz), 7.73 (1H, brs), 7.75 (2H, d, J = 8.3 Hz), 8.01 (1H, s), 8.02 (2H, d, J = 8.3 Hz), 8.25 (1H, s), 8.27 (1H, dd, J = 8.3 Hz, 2.6 Hz), 8.58 (1H, s). 2351 3,4-Cl₂Ph— 3,4-F₂PhCH₂— 2.31-2.40 (4H, m), 2.60-2.65 (2H, m), 2.93- 2.99 (2H, m), 3.39-3.45 (4H, m), 3.61-3.65 (2H, m), 6.95 (1H, d, J = 8.8 Hz), 7.03-7.24 (7H, m), 7.57 (1H, d, J = 8.3 Hz), 7.73 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.00 (1H, d, J = 2.1 Hz), 8.10 (1H, brs), 8.16-8.20 (1H, m), 8.26 (1H, d, J = 2.3 Hz). 2352 3,4-Cl₂Ph— 3,5-F₂PhCH₂— 2.32-2.38 (4H, m), 2.58-2.64 (2H, m), 2.89- 2.94 (2H, m), 3.40-3.46 (4H, m), 3.59-3.62 (2H, m), 6.66-6.74 (1H, m), 6.85-7.03 (5H, m), 7.17 (2H, d, J = 8.6 Hz), 7.52 (1H, d, J = 8.2 Hz), 7.71-7.75 (1H, m), 7.99 (1H, d, J = 2.0 Hz), 8.16-8.20 (1H, m), 8.28 (1H, d, J = 2.6 Hz), 8.77 (1H, brs).

TABLE 376

Example No. R₁₀₇₅ Xb₅₄ R₁₀₇₆ ¹H NMR (CDCl₃) δ ppm 2353 3,4-Cl₂Ph— —CO— —CH₃— 3.03 (2H, t, J = 5.2 Hz), 3.39 (2H, s), 3.51 (2H, s), 3.76 (2H, t, J = 5.2 Hz), 3.77 (3H, s), 6.98 (1H, d, J = 8.9 Hz), 7.15 (2H, dd, J = 8.8 Hz, 2.1 Hz), 7.30 (2H, dd, J = 8.8 Hz, 2.1 Hz), 7.59 (1H, d, J = 8.4 Hz), 7.72 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.99 (1H, d, J = 2.1 Hz), 8.15 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.29 (1H, d, J = 2.7 Hz). 2354 3,4-Cl₂Ph— —CH₂— —CH₃— 2.75 (4H, t, J = 5.0 Hz), 3.23 (4H, t, J = 5.0 Hz), 3.30 (2H, s), 3.75 (3H, s), 6.90 (1H, d, J = 9.0 Hz), 6.95 (2H, d, J = 9.0 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.58 (1H, d, J = 8.5 Hz), 7.70 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.76 (1H, brs), 7.98 (1H, d, J = 2.0 Hz), 8.15 (1H, dd, J = 9.0 Hz, 3.0 Hz), 8.23 (1H, d, J = 3.0 Hz). 2355 3,4-Cl₂Ph— —CH₂— —C₂H₅— 1.31 (3H, t, J = 7.0 Hz), 2.75 (4H, t, J = 5.0 Hz), 3.23 (4H, t, J = 5.0 Hz), 3.28 (2H, s), 4.21 (2H, q, J = 7.0 Hz), 6.90 (1H, d, J = 9.0 Hz), 6.95 (2H, d, J = 9.0 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.71 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.88 (1H, brs), 7.98 (1H, d, J = 2.0 Hz), 8.15 (1H, dd, J = 9.0 Hz, 2.5 Hz), 8.24 (1H, d, J = 2.5 Hz). 2356 4-CF₃Ph— —CH₂— —CH₃— 2.75 (4H, t, J = 5.0 Hz), 3.24 (4H, t, J = 5.0 Hz), 3.30 (2H, s), 3.75 (3H, s), 6.92 (1H, d, J = 9.0 Hz), 6.96 (2H, d, J = 9.0 Hz), 7.06 (2H, d, J = 9.0 Hz), 7.74 (1H, brs), 7.78 (2H, d, J = 8.0 Hz), 7.99 (2H, d, J = 8.0 Hz), 8.19 (1H, dd, J = 9.0 Hz, 2.5 Hz), 8.25 (1H, d, J = 2.5 Hz).

Example 2357 Production of 3,4-dichloro-N-[6-(4-{4-[(3,4-difluorobenzyl)methylamino]piperidine-1-carbonyl}phenoxy)pyridin-3-yl]benzamide

3,4-dichloro-N-{6-[4-(4-methylamino-piperidine-1-carbonyl)phenoxy]pyridin-3-yl}benzamide dihydrochloride (114 mg, 0.2 mmol) was dissolved in DMF (3 mL). To the resulting solution were added 4-bromomethyl-1,2-difluorobenzene (31 μl, 0.24 mmol) and potassium carbonate (111 mg, 0.8 mmol), and this solution was stirred for 4 hours at room temperature. The resulting reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. This residue was purified by silica gel column chromatography (chloroform:methanol=50:1), to thereby yield 60 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.64 (4H, brs), 1.84 (2H, brs), 2.20 (3H, s), 2.65-2.90 (3H, m), 3.54 (2H, s), 6.95-7.08 (4H, m), 7.13 (2H, d, J=9.3 Hz), 7.41 (2H, d, J=9.2 Hz), 7.57 (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.03 (1H, d, J=2.0 Hz), 8.15 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.30 (1H, brs), 8.31 (1H, d, J=2.2 Hz).

The following compounds were produced in the same manner as in Example 2357.

TABLE 377

Example No. R₁₀₇₇ ¹H NMR (CDCl₃) δ ppm 2358 2,4-F₂Ph— 1.66 (4H, brs), 1.91 (2H, brs), 2.25 (3H, s), 2.73-3.08 (3H, m), 3.63 (2H, s), 6.75-6.89 (3H, m), 6.97 (1H, d, J = 8.7 Hz), 7.13 (2H, d, J = 9.2 Hz), 7.42 (2H, d, J = 9.2 Hz), 7.57 (1H, d, J = 8.3 Hz), 7.76 (1H, dd, J = 8.3 Hz, 2.1 Hz), 8.04 (1H, d, J = 2.1 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.31 (1H, d, J = 2.3 Hz), 8.37 (1H, brs). 2359 2,5-F₂Ph— 1.72 (4H, brs), 1.88 (2H, brs), 2.25 (3H, s), 2.67-2.96 (3H, m), 3.62 (2H, s), 6.85-7.02 (3H, m), 7.09-7.23 (3H, m), 7.39 (2H, d, J = 8.9 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.05 (1H, d, J = 2.1 Hz), 8.12 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.31 (1H, d, J = 2.6 Hz), 8.66 (1H, brs). 2360 4-CH(CH₃)₂Ph— 1.25(6H, d, J = 6.9 Hz), 1.57-2.21 (7H, m), 2.66-3.07 (4H, m), 3.56 (2H, s), 3.90 (1H, brs), 4.66 (1H, brs), 6.90 (1H, d, J = 8.9 Hz), 7.04-7.10 (2H, m), 7.16-7.25 (4H, m), 7.31-7.36 (2H, m), 7.50 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.06- 8.10 (2H, m), 8.33 (1H, d, J = 2.5 Hz), 9.37 (1H, s). 2361 4-C(CH₃)₃Ph— 1.32 (9H, s), 1.58 (2H, brs), 1.89 (2H, brs), 2.22 (3H, s), 2.62- 3.10 (3H, m), 3.57 (2H, s), 3.92 (1H, brs), 4.69 (1H. brs), 6.92 (1H, d, J = 8.6 Hz), 7.06-7.11 (2H, m), 7.22-7.25 (2H, m), 7.32-7.37 (4H, m), 7.53 (1H, d, J = 8.6 Hz), 7.78 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.07 (1H, d, J = 2.2 Hz), 8.11 (1H, d, J = 2.7 Hz), 8.32 (1H, d, J = 2.7 Hz), 9.07 (1H, brs).

TABLE 378

Example No. R₁₀₇₈ ¹H NMR (CDCl₃) δ ppm 2362 4-CNPh— 1.54 (1H, brs), 1.86 (3H, brs), 2.20 (3H, s), 2.64-3.04 (3H, m), 3.64 (2H, s), 3.91 (1H, brs), 4.69 (1H, brs), 6.91 (1H, d, J = 8.9 Hz), 7.05-7.10 (2H, m), 7.32-7.37 (2H, m), 7.45 (2H, d, J = 8.4 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.59-7.62 (2H, m), 7.75-7.79 (1H, m), 8.05 (1H, d, J = 2.0 Hz), 8.10 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.35 (1H, d, J = 2.7 Hz), 9.31(1H, brs). 2363 Ph— 1.55 (2H, brs), 1.87 (2H, brs), 2.22 (3H, s), 2.61-2.80 (2H, m), 2.90 (1H, brs), 3.60 (2H, s), 3.93 (1H, brs), 4.72 (1H, brs), 6.98 (1H, d, J = 8.9 Hz), 7.14 (2H, d, J = 8.7 Hz), 7.18-7.37 (5H, m), 7.43 (2H, d, J = 8.7 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.02 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.4 Hz), 8.19 (1H, brs), 8.30 (1H, d, J = 2.4 Hz). 2364 2-ClPh— 1.50 (2H, brs), 1.90 (2H, brs), 2.26 (3H, s), 2.68-2.85 (2H, m), 2.98 (1H, brs), 3.70 (2H, s), 3.95 (1H, brs), 4.75 (1H, brs), 6.98 (1H, d, J = 8.7 Hz), 7.14 (2H, d, J = 8.5 Hz), 7.15-7.30 (2H, m), 7.34 (1H, dd, J = 7.2 Hz, 2.0 Hz), 7.43 (2H, d, J = 8.5 Hz), 7.47 (1H, dd, J = 7.2 Hz, 2.0 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.31 (1H, d, J = 2.8 Hz), 8.32 (1H, brs). 2365 3-ClPh— 1.50 (2H, brs), 1.87 (2H, brs), 2.21 (3H, s), 2.55-3.20 (3H, m), 3.57 (2H, s), 3.95 (1H, brs), 4.70 (1H, brs), 6.99 (1H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.7 Hz), 7.15-7.28 (3H, m), 7.33 (1H, brs), 7.44 (2H, d, J = 8.7 Hz), 7.59 (1H, d, J = 8.4 Hz), 7.74 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.02 (1H, d, J = 2.0 Hz), 8.09 (1H, brs), 8.17 (1H, dd, J = 8.8 Hz, 2.8 Hz), 8.30 (1H, d, J = 2.8 Hz). 2366 3,4-Cl₂Ph— 1.50 (2H, brs), 1.85 (2H, brs), 2.20 (3H, s), 2.60-3.15 (3H, m), 3.54 (2H, s), 3.95 (1H, brs), 4.70 (1H, brs), 6.97 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.10-7.19 (1H, m), 7.36 (1H, s), 7.41 (2H, d, J = 8.6 Hz), 7.35- 7.47 (1H, m), 7.57 (1H, d, J = 8.4 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.03 (1H, d, J = 2.1 Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.30 (1H, d, J = 2.5 Hz), 8.40 (1H, s). 2367 2,3-Cl₂Ph— 1.60 (2H, brs), 1.90 (2H, brs), 2.26 (3H, s), 2.65-3.20 (3H, m), 3.72 (2H, s), 3.90 (1H, brs), 4.72 (1H, brs), 6.97 (1H, d, J = 8.8 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.20 (1H, d, J = 8.0 Hz), 7.36 (1H, dd, J = 8.0 Hz, 1.5 Hz), 7.42 (2H, d, J = 8.6 Hz), 7.37-7.46 (1H, m), 7.57 (1H, d, J = 8.2 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.14 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 8.38 (1H, brs). 2368 2-FPh— 1.55 (2H, brs), 1.85 (2H, brs), 2.25 (3H, s), 2.50-3.20 (3H, m), 3.65 (2H, s), 3.95 (1H, brs), 4.70 (1H, brs), 6.97 (1H, d, J = 8.8 Hz), 6.95-7.17 (2H, m), 7.13 (2H, d, J = 8.7 Hz), 7.18-7.29 (1H, m), 7.32-7.45 (1H, m), 7.42 (2H, d, J = 8.7 Hz), 7.57 (1H, d, J = 8.2 Hz), 7.75 (1H, dd, J = 8.2 Hz, 2.1 Hz), 8.04 (1H, d, J = 2.1 Hz), 8.14 (1H, dd, J = 8.8 Hz, 2.5 Hz), 8.30 (1H, d, J = 2.5 Hz), 8.34 (1H, brs). 2369 2-CH₃Ph— 1.67 (4H, brs), 1.89 (2H, brs), 2.19 (3H, s), 2.36 (3H, s), 2.67-2 96 (3H, m), 3.57 (2H, s), 6.96 (1H, d, J = 8.7 Hz), 7.07-7.26 (6H, m), 7.41 (2H, d, J = 8.1 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.05 (1H, d, J = 2.0 Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.31 (1H, d, J = 2.6 Hz), 8.51 (1H, brs).

TABLE 379

Example No. R₁₀₇₉ Form ¹H NMR (solvent) δ ppm 2370 3,5-(CH₃O)₂Ph— hydro- (DMSO-d₆) 1.67-1.93 (2H, m), 2.08-2.30 (2H, m), chloride 2.61 (3H, d, J = 4.8 Hz), 2.95 (1H, brs), 3.31-3.75 (4H, m), 3.77 (6H, s), 4.02-4.18 (1H, m), 4.31-4.45 (1H, m), 6.57 (1H, t, J = 2.0 Hz), 6.83 (2H, d, J = 2.0 Hz), 7.16 (1H, d, J = 8.7 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.49 (2H, d, J = 8.6 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.97 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.24 (1H, d, J = 2.1 Hz), 8.24 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.55 (1H, d, J = 2.6 Hz), 10.64 (1H, brs). 2371 3-CH₃OPh— free (CDCl₃) 1.60 (2H, brs), 1.87 (2H, brs), 2.23 (3H, s), 2.52 3.20 (3H, m), 3.58 (2H, s), 3.81 (3H, s), 3.95 (1H, brs), 4.70 (1H, brs), 6.75-6.90 (3H, m), 6.97 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8 0 Hz), 7.41 (2H, d, J = 8.6 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.30 (1H, d, J = 2.6 Hz), 8.36 (1H, brs). 2372 3-CH₃Ph— free (CDCl₃) 1.61 (4H, brs), 1.88 (2H, brs), 2.22 (3H, s), 2.35 (3H, s), 2.68-3.01 (3H, m), 3.56 (2H, s), 6.98 (1H, d, J = 8.9 Hz), 7.06-7.29 (6H, m), 7.42 (2H, d, J = 8.6 Hz), 7.58 (1H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 8.3 Hz, 2.0 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.31 (1H, d, J = 2.3 Hz), 8.38 (1H, brs). 2373 3,5-F₂Ph— free (CDCl₃) 1.42-1.96 (4H, m), 2.21 (3H, s), 2.65-3.10 (3H, m), 3.56 (2H, s), 3.90 (1H, brs), 4.68 (1H, brs), 6.64- 6.70 (1H, m), 6.85-6.92 (3H, m), 7.04-7.09 (2H, m), 7.31- 7.36 (2H, m), 7.50 (1H, d, J = 8.4 Hz), 7.74-7.79 (1H, m), 8.05-8.10 (2H, m), 8.33 (1H, d, J = 2.5 Hz), 9.30 (1H, brs). 2374 3,4-(CH₃)₂Ph— free (CDCl₃) 1.59 (4H, brs), 1.90-1.98 (2H, m), 2.22 (3H, s), 2.25 (3H, s), 2.26 (3H, s), 2.67-2.97 (3H, m), 3.59 (2H, s), 6.99 (1H, d, J = 8.7 Hz), 7.05-7.10 (3H, m), 7.15 (2H, d, J = 9.4 Hz), 7.44 (2H, d, J = 9.4 Hz), 7.59 (1H, d, J = 8.3 Hz), 7.74 (1H, dd, J = 8.3 Hz, 2.2 Hz), 8.02 (1H, d, J = 2.0 Hz), 8.03 (1H, brs), 8.18 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.31 (1H, d, J = 2.8 Hz). 2375 3-FPh— free (CDCl₃) 1.59-1.85 (6H, m), 2.22 (3H, s), 2.67-2.99 (3H, m), 3.59 (2H, s), 6.94-6.97 (2H, m), 7.05-7.13 (5H, m), 7.39 (2H, d, J = 8.4 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.05 (1H, d, J = 2.0 Hz), 8.13 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.31 (1H, d, J = 2.5 Hz), 8.63 (1H, brs). 2376 2,6-F₂Ph— free (CDCl₃) 1.65 (4H, brs), 1.81-1.91 (2H, m), 2.28 (3H, s), 2.69-3.03 (3H, m), 3.69 (2H, s), 6.83-6.92 (3H, m), 6.99 (1H, d, J = 8.9 Hz), 7.15 (2H, d, J = 9.2 Hz), 7.44 (2H, d, J = 9.2 Hz), 7.59 (1H, d, J = 8.4 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.03 (1H, d, J = 2.2 Hz), 8.17 (1H, brs), 8.18 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.31 (1H, d, J = 2.6 Hz).

TABLE 380

Example No. R₁₀₈₀ mp (° C.) or MS 2377 4-CF₃OPh— mp 180-181 2378 2-NO₂Ph— MS 634 (M⁺ + H) 2379 3-NO₂Ph— MS 634 (M⁺ + H) 2380 4-NO₂Ph— MS 634 (M⁺ + H) 2381 2-CF₃Ph— MS 657 (M⁺ + H) 2382 3-CF₃Ph— MS 657 (M⁺ + H) 2383 4-CF₃Ph— MS 657 (M⁺ + H) 2384 2-CF₃OPh— MS 673 (M⁺ + H) 2385

MS 647 (M⁺ + H) 2386 4-biphenylyl MS 665 (M⁺ + H) 2387

MS 647 (M⁺ + H) 2388

MS 699 (M⁺ + H) 2389 2-pyridyl MS 590 (M⁺ + H) 2390 2-quinolyl MS 640 (M⁺ + H) 2391

MS 671 (M⁺ + H) 2392

MS 609 (M⁺ + H) 2393 2,4-Cl₂Ph— MS 657 (M⁺ + H) 2394 2,5-Cl₂Ph— MS 657 (M⁺ + H) 2395 2,6-Cl₂Ph— MS 657 (M⁺ + H)

TABLE 381

Example No. R₁₀₈₁ Xb₅₅ Xb₅₆ R₁₀₈₂ mp (° C.) or MS 2396 —H none none Ph— mp 155-158 2397 —F —(CH₂)₂— —CO— Ph— MS 634 (M⁺ + H) 2398 —F —(CH₂)₂— —CO— 2-ClPh— MS 668 (M⁺ + 1) 2399 —F —(CH₂)₂— —CO— 3-ClPh— MS 668 (M⁺ + H) 2400 —F —(CH₂)₂— —CO— 4-ClPh— MS 668 (M⁺ + H) 2401 —F —(CH₂)₂— —CO— 2,3-Cl₂Ph— MS 702 (M⁺ + 1) 2402 —F —(CH₂)₂— —CO— 2,4-Cl₂Ph— MS 701 (M⁺) 2403 —F —(CH₂)₂— —CO— 2,5-Cl₂Ph— MS 702 (M⁺ + 1) 2404 —F —(CH₂)₂— —CO— 2,6-Cl₂Ph— MS 702 (M⁺ + H) 2405 —F —(CH₂)₂— —CO— 3,4-Cl₂Ph— MS 703 (M⁺) 2406 —F —(CH₂)₂— —CO— 3-pyridyl MS 634 (M⁺) 2407 —F —(CH₂)₂— —CO— 2-quinolyl MS 685 (M⁺ + H) 2408 —F —(CH₂)₂— —CO—

MS 716 (M⁺ + H) 2409 —F —(CH₂)₂— —CO—

MS 654 (M⁺ + H) 2410 —F —(CH₂)₂— —CO—

MS 730 (M⁺ + H) 2411 —F —(CH₂)₂— —CO— 3-CH₃OPh— MS 662 (M⁺ − 1) 2412 —F —(CH₂)₂— —CO— 3,5-(CH₃O)₂Ph— MS 693 (M⁺) 2413 —F —(CH₂)₂— —CO— 2-CH₃Ph— MS 648 (M⁺ + H) 2414 —F —(CH₂)₂— —CO— 3-CH₃Ph— MS 648 (M⁺ + H) 2415 —F —(CH₂)₂— —CO— 4-CH₃Ph— MS 648 (M⁺ + H) 2416 —F —(CH₂)₂— —CO— 3,4-(CH₃)₂Ph— MS 662 (M⁺ + 1) 2417 —F —(CH₂)₂— —CO— 2-FPh— MS 652 (M⁺ + H) 2418 —F —(CH₂)₂— —CO— 3-FPh— MS 652 (M⁺ + H) 2419 —F —(CH₂)₂— —CO— 4-FPh— MS 652 (M⁺ + 1) 2420 —F —(CH₂)₂— —CO— 2 4 F₂Ph— MS 670 (M⁺ + H) 2421 —F —(CH₂)₂— —CO— 2,5-F₂Ph— MS 670 (M⁺ + H) 2422 —F —(CH₂)₂— —CO— 2,6-F₂Ph— MS 671 (M⁺ + 2) 2423 —F —(CH₂)₂— —CO— 3,4-F₂Ph— MS 670 (M⁺ + H) 2424 —F —(CH₂)₂— —CO— 3,5-F₂Ph— MS 670 (M⁺ + H)

TABLE 382

Example No. R₁₀₈₃ MS 2425 2-NO₂Ph— 679 (M⁺ + H) 2426 3-NO₂Ph— 678 (M⁺) 2427 4-NO₂Ph— 679 (M⁺ + H) 2428 2-CF₃Ph— 701 (M⁺) 2429 3-CF₃Ph— 702 (M⁺ + H) 2430 4-CF₃Ph— 701 (M⁺) 2431 4-CNPh— 659 (M⁺ + H) 2432 2-CF₃OPh— 718 (M⁺ + H) 2433 3-CF₃OPh— 718 (M⁺ + H) 2434 4-CF₃OPh— 718 (M⁺ + H) 2435

692 (M⁺ + H) 2436 4-biphenylyl 710 (M⁺ + H) 2437

692 (M⁺ + H) 2438 4-C₂H₅Ph— 662 (M⁺ + H) 2439 4-CH(CH₃)₂Ph— 676 (M⁺ + H) 2440 4-C(CH₃)₃Ph— 690 (M⁺ + H) 2441

744 (M⁺ + H) 2442 2-naphthyl 684 (M⁺ + H) 2443 2-pyridyl 635 (M⁺ + H)

Example 2444 Production of 1-(4-piperonylpiperazin-1-yl)-2-{4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]-phenylamino}ethanone

4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenylamine (4.50 g, 12.5 mmol) was dissolved in DMF (150 mL). To the resulting solution were added potassium carbonate (2.60 g, 18.8 mmol) and sodium iodide (1.87 g, 12.5 mmol), and then to this solution was added 2-chloro-1-(4-piperonylpiperazin-1-yl)ethanone (4.21 g, 12.5 mmol). The resulting solution was stirred for 11 hours under a nitrogen atmosphere at 80° C. The resulting reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=80:1), to thereby yield 5.2 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.44-2.46 (4H, m), 3.43-3.47 (4H, m), 3.69 (2H, t, J=5.0 Hz), 3.86 (2H, s), 4.91 (1H, brs), 5.02 (2H, s), 5.94 (2H, s), 6.64 (2H, d, J=8.9 Hz), 6.74-6.75 (2H, m), 6.85-6.89 (2H, m), 6.96-7.03 (4H, m), 7.55 (2H, d, J=8.4 Hz), 7.72 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.22 (1H, d, J=2.0 Hz).

Example 2445 Production of N-{6-[4-(4-thiazole-2-ylmethylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide

To a suspension of N-{6-[4-(piperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide dihydrochloride (400 mg, 0.74 mmol) in 1,2-dichloroethane (20 mL) were added 2-formylthiazole (125 mg, 1.10 mmol) and triethylamine (0.21 mL, 1.50 mmol). After the resulting solution was stirred at room temperature for 30 minutes, sodium triacetyloxy borohydride (312 mg, 1.47 mmol) was added under ice cooling. The reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. Acetic acid (0.085 mL, 1.48 mmol) was added to the reaction mixture, and stirred at room temperature for 17 hours. The reaction mixture was poured into ice water, and extracted with chloroform. The chloroform layer was washed with a saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. A significant part of the solvent was evaporated. The white precipitate was then filtered off and washed with ethyl acetate, to thereby yield 293 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.55 (4H, brs), 3.55 (4H, brs), 3.90 (2H, s), 7.15 (1H, d, J=8.7 Hz), 7.16 (2H, d, J=8.6 Hz), 7.45 (2H, d, J=8.6 Hz), 7.68 (1H, d, J=3.2 Hz), 7.73 (1H, d, J=3.2 Hz), 7.94 (2H, d, J=8.1 Hz), 8.17 (2H, d, J=8.1 Hz), 8.26 (1H, dd, J=8.7 Hz, 2.3 Hz), 8.55 (1H, d, J=2.3 Hz), 10.68 (1H, s).

The following compounds were produced in the same manner as in Example 2445.

TABLE 383

Example No. R₁₀₈₄ R₁₀₈₅ ¹H NMR (solvent) δ ppm 2446 3,4-Cl₂Ph— 3,4-(CH₃)₂Ph— (CDCl₃) 2.27 (3H, s), 2.29 (3H, s), 2.42 (4H, brs), 3.49 (2H, s), 3.70 (4H, brs), 6.90 (1H, d, J = 8.9 Hz), 7.05-7.10 (5H, m), 7.34-7 36 (2H, m), 7.50 (1H, d, J = 8.4 Hz), 7.75-7.79 (1H, m), 8.00-8.14 (2H, m), 8.33 (1H, d, J = 2.7 Hz), 9.30 (1H, brs). 2447 4-CF₃Ph— 2-FPh— (CDCl₃) 2.50 (4H, brs), 3.55 (2H, brs), 3.70 (2H, brs), 3.62 (2H, s), 6.98 (1H, d, J = 8.8 Hz), 6.95-7.17 (2H, m), 7.12 (2H, d, J = 8.7 Hz), 7.20-7.41 (2H, m), 7.40 (2H, d, J = 8.7 Hz), 7.76 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz), 8.19 (1H, dd, J = 8.8 Hz, 2.8 Hz), 8.31 (1H, s), 8.32 (1H, d, J = 2.8 Hz). 2448 4-CF₃Ph— 3-pyridyl (CDCl₃) 2.46 (4H, brs), 3.55 (2H, s), 3.58-3.73 (4H, m), 6.97 (1H, d, J = 8.7 Hz), 7.10-7.15 (2H, m), 7.25- 7.30 (1H, m), 7.38-7.43 (2H, m), 7.65-7.69 (1H, m), 7.74 (2H, d, J = 8.1 Hz), 8.03 (2H, d, J = 8.1 Hz) 8.19- 8.23 (1H, m), 8.32 (1H, d, J = 2.3 Hz), 8.51-8.53 (1H, m), 8.54 (1H, d, J = 1.5 Hz), 8.62 (1H, brs). 2449 4-CF₃Ph— cyclohexyl (DMSO-d₆) 0.60-1.90 (11H, m), 2.10 (2H, d, J = 7.2 Hz), 2.34 (4H, brs), 3.50 (4H, brs), 7.15 (1H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.7 Hz), 7.94 (2H, d, J = 8.1 Hz), 8.17 (2H, d, J = 8.1 Hz), 8.26 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.55 (1H, d, J = 2.7 Hz), 10.66 (1H, s). 2450 4-CF₃Ph— 3-furyl (CDCl₃) 2.46 (4H, brs), 3.42 (2H, s), 3.40-3.90 (4H, m), 6.39 (1H, brs), 6.98 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.34 (1H, brs), 7.33-7.42 (1H, m), 7.41 (2H, d, J = 8.7 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.20 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.29 (1H, s), 8.32 (1H, d, J = 2.5 Hz). 2451 4-CF₃Ph— 4-pyridyl (CDCl₃) 2.45 (4H, brs), 3.41-3.81 (6H, m), 6.95 (1H, d, J = 8.9 Hz), 7.08-7.13 (2H, m), 7.28 (2H, d, J = 5.9 Hz), 7.35-7.40 (2H, m), 7.70 (2H, d, J = 8.4 Hz), 8.02 (2H, d, J = 8.4 Hz), 8.21 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.33 (1H, d, J = 2.7 Hz), 8.53-8.55 (2H, m), 9.02 (1H, s). 2452 4-CF₃Ph— 2-furyl (CDCl₃) 2.50 (4H, brs), 3.59 (2H, s), 3.73 (4H, brs), 6.23 (1H, d, J = 3.0 Hz), 6.33 (1H, dd, J = 3.0 Hz, 2.0 Hz), 6.99 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.8 Hz) 7.41 (2H, d, J = 8.8 Hz), 7.35-7.48 (1H, m) 7.76 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.20 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.24 (1H, brs), 8.32 (1H, d, J = 2.5 Hz) 2453 4-CF₃Ph— 4-NO₂Ph— (CDCl₃) 2.48 (4H, brs), 3.63 (2H, s), 3.73 (4H, brs), 7.00 (1H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.7 Hz), 7.53 (2H, d, J = 8.4 Hz), 7.76 (2H, d, J = 8.0 Hz), 8.01 (2H, d, J = 8.0 Hz), 8.15 (1H, brs), 8.20 (2H, d, J = 8.4 Hz), 8.21 (1H, dd, J = 8.8 Hz, 2.5 Hz), 8.32 (1H, d, J = 2.5 Hz).

TABLE 384

Example No. R₁₀₈₆ R₁₀₈₇ mp (° C.) or ¹H NMR (solvent) δ ppm 2454 4-CF₃Ph— ¹H NMR (CDCl₃) 2.43 (4H, brs), 3.46 (2H, s) 3.55 (4H, brs), 3.65 (3H, s), 5.95-6.08 (2H, m), 6.61 (1H, t, J = 2.2 Hz), 6.98 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.02 (2H, d J = 8.1 Hz), 8.20 (1H, dd, J = 8 9 Hz, 2.5 Hz), 8.25 (1H, brs), 8.31 (1H, d, J = 2.5 Hz). 2455 4-CF₃Ph— 2-pyridyl mp 175-176 2456 4-CF₃Ph— 4-OHPh— ¹H NMR (DMSO-d₆) 2.36 (4H, brs), 3.32 (2H, s), 3.49 (4H, brs), 6.70 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J = 8.4 Hz), 7.15 (1H, d, J = 8.9 Hz), 7.16 (2H, d, J = 8.6 Hz) 7.43 (2H, d, J = 8.6 Hz), 7.94 (2H, d, J = 8.0 Hz), 8.17 (2H, d, J = 8.0 Hz), 8.26 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.54 (1H, d, J = 2.5 Hz), 9.27 (1H, s), 10.66 (1H, s). 2457 4-CF₃Ph— 2-OHPh— ¹H NMR (CDCl₃) 2.59 (4H, brs), 3.68 (4H, brs), 3.75 (2H, s), 6.72-6.88 (2H, m), 6.92-710 (1H, m), 7.01(1H, d, J = 8.8 Hz), 7.15 (2H, d, J = 8.8 Hz), 7.10-7.25 (1H, m), 7.44 (2H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.01 (2H, d, J = 8.1 Hz), 8.12 (1H, brs), 8.22 (1H, dd, J = 8.8 Hz, 2.3 Hz), 8.31 (1H, d, J = 2.3 Hz). 2458 4-CF₃Ph— 4-AcNHPh— 1H NMR (DMSO-d₆) 2.02 (3H, s), 2.38 (4H, brs), 3.45 (2H, s), 3.45 (4H, brs), 7.15 (1H, d. J = 8.9 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.52 (2H, d, J = 8.4 Hz), 7.94 (2H, d, J = 8.1 Hz), 8.17 (2H, d, J = 8.1 Hz), 8.26 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.54 (1H, d, J = 2.6 Hz), 9.90 (1H, s), 10.66 (1H, s). 2459 4-CF₃Ph— 2,3-(CH₃)₂Ph— ¹H NMR (CDCl₃) 2.25 (3H, s), 2.28 (3H, s), 2.42 (4H, brs), 3.47 (2H, s), 3.67 (4H, brs), 6.95 (1H, d, J = 8.7 Hz), 6.95-7.12 (3H, m), 7.10 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz), 7.73 (2H, d, J = 8.1 Hz), 8.00 (2H, d, J = 8.1 Hz), 8.17 (1H, dd, J = 8.7 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 8.43 (1H, s). 2460 4-CF₃Ph— 3-thienyl ¹H NMR (CDCl₃) 2.45 (4H, brs), 3.55 (2H, brs), 3.56 (2H, s), 3.72 (2H, brs), 6.97 (1H, d, J = 8.9 Hz), 7.05 (1H, dd, J = 5.0 Hz, 1.1 Hz), 7.08-7.17 (1H, m), 7.12 (2H, d, J = 8.7 Hz), 7.29 (1H, dd, J = 5.0 Hz, 3.0 Hz), 7.39 (2H, d, J = 8.7 Hz), 7.75 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.19 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.32 (1H, d, J = 2.8 Hz), 8.41 (1H, brs). 2461 3,4-Cl₂PH— 3-pyridyl ¹H NMR (CDCl₃) 2.46 (4H, brs), 3.46 (2H, s), 3.55- 3.80 (4H, m), 6.96 (1H, d, J = 8.9 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.26-7.30 (1H, m), 7.40 (2H, d, J = 8.4 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.65-7.78 (2H, m), 8.04 (1H, d, J = 2.2 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.29 (1H, d, J = 2.2 Hz), 8.51-8.56 (2H, m), 8.61 (1H, brs). brs), 3.47 (2H, s), 3.67 (4H, brs), 6.95 (1H, d, J = 8.7 Hz), 6.95-7.12 (3H, m), 7.10 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz), 7.73 (2H, d, J = 8.1 Hz), 8.00 (2H, d, J = 8.1 Hz), 8.17 (1H, dd, J =8.7 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 8.43 (1H, s).

TABLE 385

Example No. R₁₀₈₈ R₁₀₈₉ Form ¹H NMR (solvent) ppm 2462 4-CF₃Ph— cyclopropyl free (CDCl₃) 0.11 (2H, dd, J = 10.5 Hz, 4.5 Hz), 0.54 (2H, dd, J = 12.5 Hz, 6.5 Hz), 0.77-0.93 (1H, m), 2.29 (2H, d, J = 6.5 Hz), 2.52 (4H, brs), 3.55 (2H, brs), 3.75 (2H, brs), 6.98 (1H, d, J = 8.9 Hz), 7.14 (2H, d, J = 8.7 Hz), 7.42 (2H, d, J = 8.7 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.03 (2H, d, J = 8.1 Hz), 8.20 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.33 (1H,d, J = 2.5 Hz), 8.36 (1H, brs). 2463 4-CF₃Ph— 3-OHPh— hydro- (DMSO-d₆) 2.90-3.70 (6H, m), 3.90- chloride 4.20 (2H, m), 4.24 (2H, d, J = 3.9 Hz), 6.86 (1H, dd, J = 8.1 Hz, 1.7 Hz), 6.97 (1H, brs), 7.01 (1H, d, J = 7.7 Hz), 7.16 (1H, d, J = 8.9 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.52 (2H, d, J = 8.6 Hz). 7.94 (2H, d, J = 8.1 Hz), 8.20 (2H, d, J = 8.1 Hz), 8.29 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.58 (1H, d, J = 2.5 Hz), 10.77 (1H, s). 2464 4-CF₃Ph— —C(CH₃)₃ free (CDCl₃) 0.88 (9H, s), 2.09 (2H, s), 2.52 (4H, brs), 3.49 (2H, brs), 3.68 (2H, brs), 6.97 (1H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.75 (2H, d, J = 8.1 Hz), 8.03 (2H, d, J = 8.1 Hz), 8.19 (1H, dd, J = 8.8 Hz, 2.5 Hz), 8.33 (1H, d, J = 2.5 Hz), 8.47 (1H, s). 2465 4-CF₃Ph— free (CDCl₃) 2.42 (3H, s) 2.59 (4H, brs), 348- 3.76 (4H, m), 3.91 (2H, s), 4.56 (2H, s), 7.00 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.39 (2H, d, J = 8.6 Hz), 7.71 (2H, d, J = 8.3 Hz), 7.79 (1H, s), 8.00 (2H, d, J = 8.1 Hz), 8.22-8.29 (2H, m), 8.81 (1H, brs). 2466 4-CF₃Ph— free (CDCl₃) 2.55 (3H, s), 2.35-2.70 (4H, m), 3.66 (2H, s), 3.40-3.95 (4H, m), 6.93 (1H, d, J = 8.7 Hz), 7.05 (1H, d, J = 7.6 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.22 (1H, d, J = 7.6 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.56 (1H, t, J = 7.6 Hz), 7.75 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz), 8.21 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.31 (1H, d, J = 2.8 Hz), 8.38 (1H, s). 2467 4-Cl₂Ph— 4-AcNHPh— free (DMSO-d₆) 2.02 (3H, s), 2.38 (4H, brs), 3.44 (2H, s), 3.55 (4H, brs), 7.14 (1H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.7 Hz), 7.52 (2H, d, J = 8.4 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.95 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.22 (1H, d, J = 2.0 Hz), 8.23 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.51 (1H, d, J = 2.6 Hz), 9.90 (1H, s), 10.59 (1H, s).

TABLE 386

Example No. Xb₅₇ R₁₀₉₀ R₁₀₉₁ Xb₅₈ Form ¹H NMR (solvent) δ ppm 2468 —NH— —H

—CH₂— trihydro- chloride (DMSO-d₆) 2.60-3.20 (7H, m), 3.22-3.60 (3H, m), 3.71 (3H, s), 4.10 (1H, d, J = 13.2 Hz), 4.30 (2H, d, J = 4.8 Hz), 4.48 (1H, d, J = 13.2 Hz). 6.05 (1H, t, J = 2.5 Hz), 6.32 (1H, dd, J = 3.6 Hz, 1.9 Hz), 6.87 (1H, t, J = 2.5 Hz), 7.04 (2H, d, J = 8.4 Hz), 7.06 (1H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.93 (2H, d, J = 8.5 Hz), 8.19 (2H, d, J =8.5 Hz), 8.22 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.51 (1H, d, J = 2.6 Hz), 10.70 (1H, s). 2469 —NH— —H 3-furylmethyl —CH₂— free (CDCl₃) 2.25-2.45 (4H, m), 2.60 (2H, t, J = 7.7 Hz), 2.93 (2H, t, J = 7.7 Hz), 3.37 (2H, s), 3.40 (2H, t, J = 5.0 Hz), 3.60 (2H, t, J = 5.0 Hz), 6.37 (1H, d, J = 1.5 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.02 (2H, d, J = 8.6 Hz), 7.19 (2H, d, J = 8.6 Hz), 7.33 (1H, s), 7.39 (1H, t, J = 1.5 Hz), 7.73 (2H, d, J = 8.1 Hz), 8.01 (2H, d, J = 8.1 Hz), 8.21 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.28 (1H, d, J = 2.6 Hz), 8.46 (1H, s). 2470 —NH— —H furfuryl —CH₂— free (CDCl₃) 2.31-2.52 (4H, m), 2.60 (2H, t, J = 7.2 Hz), 2.93 (2H, t, J = 7.2 Hz), 3.43 (2H, t, J = 5.0 Hz), 3.55 (2H, s), 3.63 (2H, t, J = 5.0 Hz), 6.21 (1H, d, J = 2.6 Hz), 6.32 (1H, d, J = 3.0 Hz), 6.94 (1H, d, J = 8.9 Hz), 7.02 (2H, d, J = 8.5 Hz), 7.19 (2H, d, J = 8.5 Hz), 7.38 (1H, d, J = 2.8 Hz), 7.74 (2H, d, J = 8.0 Hz), 8.00 (2H, d, J = 8.0 Hz), 8.21 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.28 (1H, d, J = 2.5 Hz), 8.35 (1H, s). 2471 none —CH₃ piperonyl —N(CH₃)— free (CDCl₃) 2.12 (3H, s), 2.42- 2.45 (4H, m), 3.03 (3H, s), 3.44 (2H, s), 3.47-3.52 (2H, m), 3.62-3.65 (2H, m), 4.09 (2H, s), 5.95 (2H, s), 6.54-6.59 (2H, m), 6.71-6.77 (2H, m), 6.85 (1H, s), 6.92-6.96 (2H, m), 7.75 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.1 Hz), 8.17 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.58 (1H, d, J = 2.1 Hz).

TABLE 387

Example No. R₁₀₉₂ Xb₅₉ Xb₆₀ R₁₀₉₃ ¹H NMR (DMSO-d₆) δppm 2472 3,4-Cl₂Ph— —NH— none benzyl 1.55-1.82(4H, m), 1.96(2H, t, J = 10.5 Hz), 2.21-2.40(1H, m), 2.87(2H, d, J = 10.5 Hz), 3.47(2H, s), 7.02(1H, d, J = 8.9 Hz), 7.05(2H, d, J = 9.1 Hz), 7.18- 7.42(5H, m), 7.62(2H, d, J = 9.1 Hz), 7.84(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.17(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, d, J = 2.0 Hz), 8.46(1H, d, J = 2.6 Hz), 9.89(1H, s), 10.53(1H, s). 2473 3,4-Cl₂Ph— —NH— none 3-furylmethyl 1.55-1.85(4H, m), 1.85-2.07(2H, m), 2.18-2.40(1H, m), 2.80- 3.00(2H, m), 3.32(2H, s), 6.44(1H, s), 7.02(1H, d, J = 8.9 Hz), 7.05(2H, d, J = 8.9 Hz), 7.57(1H, s), 7.57-7.66(1H, m), 7.62(2H, d, J = 8.9 Hz), 7.84(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.17(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, d, J = 2.0 Hz), 8.45(1H, d, J = 2.6 Hz), 9.89(1H, s), 10.54(1H, s). 2474 4-CF₃Ph— none —N(CH₃)— benzyl 1.50-2.30(6H, m), 2.84(5H, brs), 3.44(2H, brs), 4.27(1H, brs), 7.16(3H, d, J = 8.6 Hz), 7.18- 7.39(5H, m), 7.41(2H, d, J = Hz), 7.95(2H, d, J = 8.1 Hz), 8.17(2H, d, J = 8.1 Hz), 8.27(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.56 (1H, d, J = 2.5 Hz), 10.68(1H, s). 2475 4-CF₃Ph— none —N(CH₃)— 3-furylmethyl 1.50-2.20(6H, m), 2.83(3H, s), 2.72-3.02(2H, m), 3.30(2H, d, J = 3.5 Hz), 4.28(1H, brs), 6.41(1H, s), 7.15(1H, d, J = 8.8 Hz), 7.16(2H, d, J = 8.4 Hz), 7.41(2H, d, J = 8.4 Hz)7.53 (1H, s) 7.60(1H, s), 7.95(2H, d, J = 8.1 Hz), 8.17(2H, d, J = 8.1 Hz), 8.27(1H, dd, J = 8.8 Hz, 2.5 Hz), 8.55(1H, d, J = 2.5 Hz), 10.68 (1H, s).

TABLE 388

Example No. R₁₀₉₄ ¹H NMR (CDCl₃) δppm 2476 cyclohexyl 1.00-1.40(5H, m), 1.52-1.70(1H, m), 1.70-1.92(4H, m), 2.21-2.40(1H, m), 2.57 (4H, brs), 3.52(2H, brs), 3.73(2H, brs), 6.98(1H, d, J = 8.9 Hz), 7.13(2H, d, J = 8.8 Hz), 7.41(2H, d, J = 8.8 Hz), 7.76(2H, d, J = 8.2 Hz), 8.03(2H, d, J = 8.2 Hz), 8.19 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.33(1H, d, J = 2.5 Hz), 8.36(1H, brs). 2477

1.40-1.85(4H, m), 2.38-2.60(1H, m), 2.57(4H, brs), 3.38(2H, t, J = 11.0 Hz), 3.72 (4H, brs), 4.03(2H, dd, J = 11.0 Hz, 3.5 Hz), 7.00(1H, d, J = 8.7 Hz), 7.15(2H, d, J = 8.7 Hz), 7.43(2H, d, J = 8.7 Hz), 7.77(2H, d, J = 8.5 Hz), 8.02(2H, d, J = 8.5 Hz), 8.16(1H, brs), 8.21(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.32(1H, d, J = 2.5 Hz). 2478 cyclopropyl 0.33-0.58(4H, m), 1.45-1.72(1H, m), 2.62(4H, brs), 3.49(2H, brs), 3.68(2H, brs), 7.00(1H, d, J = 8.9 Hz), 7.15(2H, d, J = 8.4 Hz), 7.43(2H, d, J = 8.4 Hz), 7.77(2H, d, J = 8.4 Hz), 8.02(2H, d, J = 8.4 Hz), 8.21(1H, s), 8.21(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.33(1H, d, J = 2.6 Hz).

TABLE 389 Ex- ample ¹H NMR No. Chemical structure (solvent) δppm 2479

(DMSO-d₆) 2.77-3.10 (2H, m), 3.17-3.63(4H, m), 3.71-3.89(1H, m), 4.18(2H, s), 4.24(2H, s), 4.27-4.44(1H, m), 6.07 (2H, s), 6.92-7.06(2H, m), 7.09(3H, d, J = 8.6 Hz), 7.22(1H, s), 7.28(2H, d, J = 8.6 Hz), 7.92(2H, d, J = 8.0 Hz), 8.18(2H, d, J = 8.0 Hz), 8.24(1H, dd, J = 8.8 Hz, 2.5 Hz), 8.53(1H, d, J = 2.5 Hz), 10.69(1H, s). 2480

(CDCl₃) 2.25-2.52(4H, m), 2.77-2.95 (2H, m), 3.12-3.29(1H, m), 3.29- 3.46 (1H, m), 3.41(2H, s), 3.43-3.59(1H, m), 3.65-3.84(2H, m), 5.30 (1H, brs), 5.92 (2H, s), 6.73(2H, s), 6.84(1H, s), 6.95 (1H, d, J = 9.0 Hz), 7.05(2H, d, J = 8.4 Hz), 7.23(2H, d, J = 8.4 Hz), 7.75(2H, d, J = 8.1 Hz), 7.98(2H, d, J = 8.1 Hz), 8.03(1H, brs), 8.20(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.22(1H, s). 2481

(CDCl₃) 1.32-1.44(2H, m), 1.83-2.02 (3H, m), 2.30(2H, d, J = 6.8 Hz), 2.42-2.47(4H, m), 2.69 (2H, t, J = 12.0 Hz), 3.48-3.66(8H, m), 6.86- 6.99(6H, m), 7.25-7.32 (7H, m), 7.50(2H, d, J = 8.6 Hz), 7.98(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.59 (1H, d, J = 2.0 Hz).

Example 2482 Production of N-(6-{4-[4-((1S,2S)-2-hydroxycyclohexyl)piperazine-1-carbonyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide

To a solution of N-{6-[4-(piperazine-1-carbonyl)phenoxy]-pyridin-3-yl}-4-trifluoromethylbenzamide (430 mg, 0.91 mmol) in methanol was added 1,2-epoxycyclohexane (180 mg, 1.83 mmol), and the resulting solution was stirred for 1 day under reflux. The resulting reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=35:1), and then ethyl acetate was added. The precipitated white powder was filtered off and washed with ethyl acetate, to thereby yield 284 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.03-1.38 (4H, m), 1.42-1.88 (3H, 2.06-2.35 (2H, m), 2.31 (2H, brs), 2.74 (2H, brs), 3.30-4.00 (6H, m), 7.00 (1H, d, J=8.9 Hz), 7.15 (2H, d, J=8.7 Hz), 7.43 (2H, d, J=8.7 Hz), 7.77 (2H, d, J=8.1 Hz), 8.02 (2H, d, J=8.1 Hz), 8.21 (1H, brs), 8.22 (1H, dd, J=8.9 Hz, 2.7 Hz), 8.33 (1H, d, J=2.7 Hz).

Example 2483 Production of 3,4-dichloro-N-[6-({4-[3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenyl}methylamino)pyridin-3-yl]benzamide dioxalate

To a solution of 3,4-dichloro-N-(6-{4-[3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenylamino}-pyridin-3-yl)benzamide (250 mg, 0.395 mmol) in methanol (3 mL) were added acetic acid (0.500 mL) and 37% aqueous formaldehyde (0.640 mL, 7.89 mmol), and the resulting solution was stirred for 30 minutes at 50° C. To the reaction solution was added sodium cyanoborohydride (0.160 g, 2.55 mmol) at room temperature, and stirred for 8 hours at 50° C. Water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1), to yield a free form. This free form was dissolved in isopropanol (5 mL) and oxalic acid dihydrate (70 mg, 0.555 mmol) by heating. The solvent was evaporated, and the resulting solid was recrystallized from isopropanol, to thereby yield 0.193 g of the title compound.

Appearance: Pale yellow powder

Melting point: 127-129° C.

The following compound was produced in the same manner as in Example 2483.

Example 2484 2-(Ethyl{4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenyl}amino)-1-(4-piperonylpiperazin-1-yl)ethanone

¹H NMR (CDCl₃) δ 1.18 (3H, t, J=7.1 Hz), 2.41-2.44 (4H, m), 3.39-3.47 (4H, m), 3.51 (2H, brs), 3.64 (2H, brs), 4.03 (2H, s), 5.03 (2H, s), 5.94 (2H, s), 6.68 (2H, d, J=9.1 Hz), 6.73-6.74 (2H, m), 6.85-6.88 (2H, m), 6.99 (2H, d, J=9.1 Hz), 7.01 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.7 Hz), 7.71 (1H, dd, J=8.6 Hz, 2.5 Hz), 8.22 (1H, d, J=2.3 Hz).

Example 2485 Production of 3,4-dichloro-N-[6-(4-thiomorpholine-4-ylmethylphenoxy)pyridin-3-yl]benzamide monohydrochloride

3,4-dichloro-N-[6-(4-chloromethylphenoxy)pyridin-3-yl]benzamide (0.61 g, 1.5 mmol) was dissolved in DMF (5 mL). To the resulting solution were added triethylamine (0.84 mL, 6.0 mmol) and thiomorpholine (0.15 mL, 1.5 mmol), and this solution was stirred overnight at 40° C. The resulting reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. This residue was purified by silica gel column chromatography (chloroform:methanol=80:1). The obtained solid (0.56 g, 1.18 mmol) was dissolved in ethyl acetate (50 mL), and a solution of 4 N hydrogen chloride in ethyl acetate (0.295 mL, 1.18 mmol) was added, and this solution was stirred for 1 hour at room temperature. The precipitated crystals were collected by suction filtration, and recrystallized from methanol, to thereby yield 0.38 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.80-2.83 (2H, m), 3.09-3.17 (4H, m), 3.61 (2H, m), 4.35 (2H, s), 7.14 (1H, d, J=8.9 Hz), 7.21 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.85 (1H, d, J=8.6 Hz), 7.96 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.23 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.24 (1H, d, J=2.0 Hz), 8.53 (1H, d, J=2.6 Hz), 10.45 (1H, brs), 10.62 (1H, brs).

The following compounds were produced in the same manner as in Example 2485.

Example 2486 3,4-Dichloro-N-(4-{4-[1-(3-imidazole-1-ylpropyl)-1,2,3,6-tetrahydropyridine-4-yl]phenoxy}phenyl)benzamide

Melting point: 169-171° C.

TABLE 390

Ex- ample mp No. R₁₀₉₅ Xb₆₁ R₁₀₉₆ Form (° C.) 2487 —F —CH₂— benzyl dihydro- 178-179 chloride 2488 —F —CH₂— piperonyl dihydro- 192-195 chloride 2489 —F —(CH₂)₂— benzyl dihydro- 208-210 chloride 2490 —F —(CH₂)₂— piperonyl dihydro- 202-205 chloride 2491 —F —(CH₂)₃— benzyl dihydro- 260-262 chloride 2492 —F —(CH₂)₃— piperonyl dihydro- 258-260 chloride 2493 —F —(CH₂)₄— benzyl dihydro- 245-248 chloride 2494 —F —(CH₂)₄— piperonyl dihydro- 256-258 chloride 2495 —H none

free 172-173 2496 —H none

free 131-134

TABLE 391

Example No. M Form mp (° C.) 2497 1 hydrochloride 165-168 2498 2 free 143-144 2499 3 oxalate 173-175 2500 4 hydrochloride 226-228

TABLE 392

Example No. M mp (° C.) 2501 1 183-185 2502 4 141-143

TABLE 393

Example No. R₁₀₉₇ R₁₀₉₈ M Form ¹H NMR (solvent) δppm 2503 3,4-Cl₂Ph— piperidino 1 free (CDCl₃) 1.42-1.58(6H, m), 2.36-2.38(4H, m), 3.44(2H, s), 6.86(1H, d, J = 8.9 Hz), 6.99(2H, dd, J = 6.6 Hz, 2.0 Hz), 7.26- 7.31(2H, m), 7.47(1H, d, J = 8.3 Hz), 7.67(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.94(1H, d, J = 2.3 Hz), 8.10(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.21(1H, d, J = 2.6 Hz), 8.69(1H, brs). 2504 3,4-Cl₂Ph— piperidino 3 dihydro- (DMSO-d₆) 1.67-1.77(6H, m), 1.99-2.10 chloride (2H, m), 2.61-3.05 (6H, m), 3.40-3.43(2H, m), 6.01(1H, brs), 7.04-7.08(3H, m), 7.28(2H, d, J = 8.6 Hz), 7.84(1H, d, J = 8.4 Hz), 7.96-8.00 (1H, m), 8.19-8.23(1H, m), 8.26(1H, d, J = 1.9 Hz), 8.51 (1H, d, J = 2.7 Hz), 10.24(1H, brs), 10.67(1H, s). 2505 3,4-Cl₂Ph— piperidino 4 free (CDCl₃) 1.40-1.50(2H, m), 1.50-1.75(8H, m), 2.25-2.50 (6H, m), 2.63(2H, t, J = 7.0 Hz), 6.93(1H, d, J = 9.0 Hz), 7.03(2H, d, J = 8.5 Hz), 7.19(2H, d, J = 8.5 Hz), 7.58(1H, d, J = 8.5 Hz), 7.71(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.82(1H, s), 7.98(1H, d, J = 2.0 Hz), 8.16(1H, dd, J = 9.0 Hz, 3.0 Hz), 8.25(1H, d, J = 3.0 Hz). 2506 3,4-Cl₂Ph— piperidino 5 free (CDCl₃) 1.20-1.80(12H, m), 2.31(2H, t, J = 7.8 Hz), 2.40 (4H, brs), 2.61(2H, t, J = 7.8 Hz), 6.94(1H, d, J = 8.8 Hz), 7.04(2H, d, J = 8.4 Hz), 7.20(2H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.98(1H, d, J = 2.3 Hz), 8.16(1H, dd, J = 8.8 Hz, 2.8 Hz), 8.24(1H, d, J = 2.8 Hz). 2507 4-CF₃Ph— morpholino 1 free (DMSO-d₆) 2.37(4H, t, J = 4.6 Hz), 3.46 (2H, s), 3.59(4H, t, J = 4.6 Hz), 7.07(3H, d, J = 8.6 Hz), 7.33(2H, d, J = 8.6 Hz), 7.93(2H, d, J = 8.6 Hz), 8.15-8.24(3H, m), 8.51(1H, d, J = 2.6 Hz), 10.63(1H, s). 2508 3,4-Cl₂Ph— morpholino 1 free (CDCl₃) 2.56(4H, t, J = 4.6 Hz), 3.60(2H, s), 3.82(4H, t J = 4.6 Hz), 7.05(1H, d, J = 8.6 Hz), 7.18(2H, dd, J = 6.6 Hz, 2.0 Hz), 7.45(2H, d, J = 8.6 Hz), 7.67(1H, d, J = 8.6 Hz), 7.80(1H, dd, J = 83 Hz, 2.0 Hz), 7.99(1H, brs), 8.07(1H, d, J = 2.0 Hz), 8.25-8.29(1H, m), 8.35(1H, d, J = 2.6 Hz). 2509 3,4-Cl₂Ph— morpholino 2 free (CDCl₃) 2.54-2.85(8H, m), 3.74-3.78(4H, m), 6.95(1H, d, J = 8.9 Hz), 7.04-7.07(2H, m), 7.22-7.26(2H, m), 7.58(1H, d, J = 8.6 Hz), 7.68-7.72(1H, m), 7.79(1H, brs), 7.98(1H, d, J = 2.0 Hz), 8.17(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz). 2510 3,4-Cl₂Ph— morpholino 3 free (CDCl₃) 1.78-1.83(2H, m), 2.34-2.45(6H, m), 2.60-2.66 (2H, m), 3.70-3.73(4H, m), 6.88(1H, d, J = 8.6 Hz), 7.00 (2H, d, J = 8.6 Hz), 7.18(2H, d, J = 8.6 Hz), 7.51(1H, d, J = 8.6 Hz), 7.66-7.70(1H, m), 7.94(1H, d, J = 2.2 Hz), 8.10-8.14(1H, m), 8.22(1H, d, J = 2.7 Hz), 8.40(1H, brs).

TABLE 394

Example No. R₁₀₉₉ M Form ¹H NMR (solvent) δppm 2511 morpholino 4 dihydro- (DMSO-d₆) 1.55-1.90(4H, m), 2.63(2H, t, J = 7.2 Hz), chloride 2.90-3.20(4H, m), 3.30-3.50(2H, m), 3.79(2H, t, J = 11.2 Hz) 3.93(2H, s), 7 04(2H, d, J = 8.2 Hz), 7.05(1H, d, J = 9.0 Hz), 7.26(2H, d, J = 8.2 Hz), 7.84(1H, d, J = 8.2 Hz), 7.98(1H, dd, J = 8.2 Hz, 2.0 Hz), 8.20(1H, dd, J = 9.0 Hz, 2.7 Hz), 8.25(1H, d, J = 2.0 Hz), 8.50(1H, d, J = 2.7 Hz), 10.65(1H, s). 2512 morpholino 5 free (CDCl₃) 1.30-1.45(2H, m), 1.45-1.75(4H, m), 2.33(2H, t, J = 7.2 Hz), 2.44(4H, t, J = 4.6 Hz), 2.62(2H, t, J = 7.7 Hz), 3.72(4H, t, J = 4.6 Hz), 6.94(1H, d, J = 9.0 Hz), 7.04(2H, d, J = 8.5 Hz), 7.20(2H, d, J = 8.5 Hz), 7.58(1H, d, J = 8.2 Hz), 7.65-7.75(2H, m), 7.98(1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 9.0 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz). 2513

3 free (CDCl₃) 1.97-2.03(2H, m), 2.67(2H, t, J = 7.6 Hz), 3.68- 3.73(2H, m), 3.88(2H, s), 6.95(1H, d, J = 8.9 Hz), 7.05(2H, d, J = 8.6 Hz), 7.21(2H, d, J = 8.6 Hz), 7.56(1H, d, J = 8.3 Hz), 7.69-7.74(2H, m), 7.98(1H, d, J = 2.3 Hz), 8.14-8.18(1H, m), 8.23(1H, d, J = 3.0 Hz). 2514

1 free (DMSO-d₆) 5.20(2H, s), 6.91(1H, s), 7.07(1H, d, J = 8.6 Hz), 7.10(2H, d, J = 8.6 Hz), 7.22(1H, s), 7.31(2H, d, J = 8.6 Hz), 7.77(1H, s), 7.84 (1H, d, J = 8.6 Hz), 7.94(1H, dd, J = 8.6 Hz, 2.0 Hz), 8.19(1H, dd, J = 8.6 Hz, 2.3 Hz), 8.22(1H, d, J = 2.0 Hz), 8.46(1H, d, J = 2.3 Hz), 10.57 (1H, s). 2515

1 hydro- chloride (DMSO-d₆) 5.48(2H, s), 7.09(1H, d, J = 8.5 Hz), 7.12(2H, d, J = 8.6 Hz), 7.38(2H, d, J = 8.6 Hz), 7.83(1H, d, J = 8.5 Hz), 7.98(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.23(1H, dd, J = 8.5 Hz, 2.3 Hz), 8.26(1H, s), 8.26(1H, d, J = 2.0 Hz), 8.51(1H, d, J = 2.3 Hz), 9.05(1H, s), 10.70(1H, s). 2516

1 free (DMSO-d₆) 5.63(2H, d, J = 8.6 Hz), 7.09(1H, d, J = 8.6 Hz), 7.11(2H, d, J = 8.6 Hz), 7.36(2H, d, J = 8.6 Hz), 7.76(1H, d, J = 1.0 Hz), 7.84(1H, d, J = 8.3 Hz), 7.94(1H, dd, J = 8.3 Hz, 2.0 Hz), 8.20(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.23(2H, s), 8.46(1H, d, J = 2.6 Hz), 10.55(1H, s). 2517

1 hydro- chloride (DMSO-d₆) 5.66(2H, s), 7.09(1H, d, J = 8.6 Hz), 7.10(2H, d, J = 8.6 Hz), 7.32(2H, d, J = 8.6 Hz), 7.83(2H, s), 7.83(1H, d, J = 8.5 Hz), 7.96 (1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1H, dd, J = 8.5 Hz, 2.3 Hz), 8.23(1H, d, J = 2.0 Hz), 8.47(1H, d, J = 2.3 Hz), 10.61(1H, s). 2518

1 hydro- chloride (DMSO-d₆) 5.34(2H, s), 6.28(1H, t, J = 2.0 Hz), 7.06(1H, d, J = 9.0 Hz), 7.07(2H, d, J = 8.6 Hz), 7.26(2H, d, J = 8.6 Hz), 7.47(1H, d, J = 2.0 Hz), 7.83(1H, d, J = 8.6 Hz), 7.85(1H, d, J = 2.0 Hz), 7.96(1H, dd, J = 8.6 Hz, 2.0 Hz), 8.20(1H, dd, J = 9.0 Hz, 2.6 Hz), 8.23(1H, d, J = 2.0 Hz), 8.47(1H, d, J = 2.6 Hz,) 10.61(1H, s), 2519

2 free (CDCl₃) 3.04(2H, t, J = 7.0 Hz), 4.17(2H, t, J = 7.0 Hz), 6.87(1H, t, J = 1.3 Hz), 6.94(1H, d, J = 8.7 Hz), 7.02(1H, brs), 7.05(4H, s), 7.30(1H, brs), 7.56(1H, d, J = 8.3 Hz), 7.75(1H, dd, J = 8.3 Hz, 2.1 Hz), 8.03(1H, d, J = 2.1 Hz), 8.17(1H, dd, J = 8.7 Hz, 2.3 Hz), 8.23(1H, d, J = 2.3 Hz), 8.61(1H, brs).

TABLE 395

Example No. R₁₁₀₀ R₁₁₀₁ ¹H NMR (solvent) δppm 2520 4-ClPh— piperonyl (CDCl₃) 2.48(8H, brs), 3.42(2H, s), 3.50(2H, s), 5.93(2H, s), 6.74 (2H, s), 6.85(1H, s), 6.94(1H, d, J = 8.6 Hz), 7.07(2H, d, J = 8.6 Hz), 7.33(2H, d, J = 8.6 Hz), 7.49(2H, d, J = 8.6 Hz), 7.73(1H, brs), 7.82(2H, d, J = 8.6 Hz), 8.18-8.24(2H, m). 2521 4-CNPh— piperonyl (CDCl₃) 2.48(8H, brs), 3.42(2H, s), 3.51(2H, s), 5.93(2H, s), 6.73-6.74(2H, m), 6.85(1H, s), 6.96(1H, d, J = 8.9 Hz), 7.07(2H, d, J = 8.6 Hz), 7.34(2H, d, J = 8.6 Hz), 7.79- 7.82(3H, m), 7.99(2H, d, J = 8.2 Hz), 8.19(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.26(1H, d, J = 2.6 Hz). 2522 3,4-Cl₂Ph— benzyl (CDCl₃) 2.51(8H, brs), 3.52(2H, s), 3.53(2H, s)6.95(1H, d, J = 8.9 Hz), 7.07(2H, d, J = 8.2 Hz), 7.26-7.36(7H, m), 7.59(1H, d, J = 8.6 Hz), 7.69-7.73(2H, m), 7.99(1H, d, J = 2.0 Hz), 8.18(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.6 Hz). 2523 3,4-Cl₂Ph— —COOC(CH₃)₃ (CDCl₃) 1.46(9H, s), 2.40(4H, t, J = 5.0 Hz), 3.43(4H, t, J = 5.0 Hz), 3.50(2H, s), 6.95(1H, d, J = 8.9 Hz), 7.08(2H, d, J = 8.6 Hz), 7.34 (2H, d, J = 8.6 Hz), 7.57(1H, d, J = 8.3 Hz), 7.70-7.74(1H, m), 8.00 (1H, d, J = 2.0 Hz), 8.07(1H, brs), 8.17-8.21(1H, m), 8.27(1H, d, J = 2.6 Hz). 2524 3,4-Cl₂Ph— —C₂H₅ (CDCl₃) 1.08(3H, t, J = 7.3 Hz), 2.38-2.49(10H, m), 3.48(2H, s), 6.88(1H, d, J = 8.9 Hz), 7.01(2H, d, J = 8.3 Hz), 7.30(2H, d, J = 8.6 Hz), 7.49(1H, d, J = 8.3 Hz), 7.66-7.70(1H, m), 7.95(1H, d, J = 2.0 Hz), 8.13(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.23(1H, d, J = 2.6 Hz), 8.58 (1H, brs). 2525 3,4-Cl₂Ph— —Ph (CDCl₃) 2.64(4H, t, J = 5.0 Hz), 3.22(4H, t, J = 5.0 Hz), 3.57(2H, s), 6.83-6.88(1H, m), 6.92-6.99(3H, m), 7.10(2H, d, J = 8.6 Hz), 7.23-7.29(2H, m), 7.39(2H, d, J = 8.6 Hz), 7.59(1H, d, J = 8.6 Hz), 7.71(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.76(1H, s), 7.99(1H, d, J = 2.0 Hz), 8.19(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.26(1H, d, J = 2.6 Hz). 2526 4-CF₃Ph— —COOC(CH₃)₃ (DMSO-d₆) 1.40(9H, s), 2.32-2.36(4H, m), 3.30-3.35(4H, m), 3.49 (2H, s), 7.06-7.09(3H, m), 7.32-7.36(2H, m), 7.94(2H, d, J = 8.4 Hz), 8.18(2H, d, J = 8.1 Hz), 8.24(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.52 (1H, d, J = 2.7 Hz), 10.64(1H, s). 2527 3,4-Cl₂Ph— —CH₃ (CDCl₃) 2.27(3H, s), 2.45(8H, brs), 3.47(2H, s), 6.87(1H, d, J = 8.9 Hz), 6.99-7.03(2H, m), 7.27-7.31(2H, m), 7.48(1H, dd, J = 8.3 Hz, 2.6 Hz), 7.68(1H, dd, J = 8.6 Hz, 2.0 Hz), 7.94(1H, d, J = 2.0 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.23(1H, d, J = 2.6 Hz), 8.76(1H, brs). 2528 3,4-Cl₂Ph— piperonyl (CDCl₃) 2.47(8H, brs), 3.42(2H, s), 3.49(2H, s), 5.93(2H, s), 6.73 (2H, d, J = 0.7 Hz), 6.84(1H, s), 6.91(1H, d, J = 8.9 Hz), 7.04(2H, d, J = 8.6 Hz), 7.31(2H, d, J = 8.6 Hz), 7.53(1H, d, J = 8.2 Hz), 7.70 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.97(1H, d, J = 2.3 Hz), 8.13-8.18(1H, m), 8.24(2H, d, J = 2.6 Hz).

TABLE 396

Example No. R₁₁₀₂ Xb₆₂ R₁₁₀₃ Form ¹H NMR (solvent) δppm 2529 3,4-Cl₂Ph— —(CH₂)₂— piperonyl free (CDCl₃) 1.97-2.01(2H, m), 2.85- 2.90(8H, m), 3.68(2H, s), 3.75(2H, s), 5.95(2H, s), 6.74- 6.84(2H, m), 6.94-6.97(2H, m), 7.08(2H, d, J = 8.6 Hz), 7.41(2H, d, J = 8.6 Hz), 7.57(1H, d, J = 8.6 Hz), 7.75(1H, dd, J = 8.6 Hz, 2.3 Hz), 8.01-8.02(2H, m), 8.20(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.31(1H, d, J = 2.6 Hz). 2530 3,4-Cl₂Ph— —(CH₂)₂— benzyl trihydro- (DMSO-d₆) 2.25(2H, brs), 3.38 chloride (4H, brs), 3.78(4H, brs), 4.38 (4H, s), 7.12-7.22(3H, m), 7.46- 7.48(3H, m), 7.62-7.67 (4H, m), 7.84(1H, d, J = 8.6 Hz), 7.98 (1H, dd, J = 8.6 Hz, 2.0 Hz), 8.22-8.27(2H, m), 8.55 (1H, d, J = 2.6 Hz), 10.68(1H, s). 2531 3,4-Cl₂Ph— —CO— benzyl free (CDCl₃) 2.66(2H, t, J = 5.9 Hz), 3.22-3.25(4H, m), 3.55(2H, s), 4.60(2H, s), 6.95(1H, d, J = 8.9 Hz), 7.08(2H, d, J = 8.6 Hz), 7.23-7.35(7H, m), 7.56(1H, d, J = 8.3 Hz), 7.72(1H, dd, J = 2.0 Hz, 8.6 Hz), 8.00(1H, d, J = 2.0 Hz), 8.10(1H, s), 8.18(1H, dd, J = 2.6 Hz, 8.6 Hz), 8.28 (1H, d, J = 2.6 Hz). 2532 4-CF₃Ph— —CH₂—

free (CDCl₃) 2.61(4H, brs), 3.38(4H, brs), 3.55(2H, s), 6.85-6.94(3H, m), 7.06-7.14 (4H, m), 7.36(2H, d, J = 8.3 Hz), 7.64(2H, d, J = 8.3 Hz), 7.70-7.75(4H, m), 7.99 (2H, t, J = 8.3 Hz), 8.24(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.40(1H, d, J = 2.6 Hz), 9.19 (1H, s). 2533 4-CF₃Ph— —CH₂—

free (CDCl₃) 2.58-2.62(4H, m), 3.14- 3.17(4H, m), 3.54(2H, s), 3.86(2H, s), 6.83-7.14 (11H, m), 7.36(2H, d, J = 8.4 Hz), 7.71 (2H, d, J = 8.3 Hz), 7.96(2H, d, J = 8.1 Hz), 8.15-8.26(3H, m).

TABLE 397

Example No. R₁₁₀₄ R₁₁₀₅ M ¹H NMR (CDCl₃) δppm 2534 3,4-Cl₂Ph— CH₃ 2 2.30(3H, s), 2.50-2.81(12H, m), 6.86(1H, d, J = 8.6 Hz), 6.98 (2H, d, J = 8.6 Hz), 7.18(2H, d, J = 8.3 Hz), 7.47(1H, d, J = 8.3 Hz), 7.67(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.94(1H, d, J = 2.0 Hz), 8.11(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.21(1H, d, J = 2.6 Hz), 8.66 (1H, brs). 2535 3,4-Cl₂Ph— piperonyl 2 2.51-2.83(12H, m), 3.43(2H, s), 5.93(2H, s) 6.74 (2H, d, J = 1.0 Hz), 6.86-7.03(4H, m), 7.20(2H, d, J = 8.3 Hz), 7.53(1H, d, J = 8.6 Hz), 7.68- 7.72(1H, m), 7.97(1H, d, J = 2.0 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.23(2H, d, J = 2.6 Hz). 2536 3,4-Cl₂Ph— —CH₃ 3 1.78-1.84(2H, m), 2.29(3H, s), 2.36-2.48(10H, m), 2.59-2.65 (2H, m), 6.89(1H, d, J = 8.4 Hz), (2H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.00(2H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.52(1H, d, J = 8.6 Hz), 7.67-7.71(1H, m), 7.96(1H, d, J = 2.2 Hz), 8.11-8.15(1H, m), 8.23(1H, d, J = 2.7 Hz), 8.31(1H, brs). 2537 3,4-Cl₂Ph— piperonyl 3 1.78-1.84(2H, m), 2.36-2.47(10H, m), 2.60-2.65 (2H, m), 3.41 (2H, s), 5.93(2H, s), 6.73(2H, d, J = 0.8 Hz), 6.85(1H, s), 6.91 (1H, d, J = 8.9 Hz), 7.02(2H, d, J = 8.4 Hz), 7.19(2H, d, J = 8.6 Hz), 7.55(1H, d, J = 8.1 Hz), 7.68-7.71(1H, m), 7.96- 7.97(2H, m), 8.I4-8.17(1H, m), 8.23(1H, d, J = 2.7 Hz). 2538 4-CF₃Ph— —COOC(CH₃)₃ 3 1.46(9H, s), 1.78-1.89(2H, m), 2.36-2.42(6H, m), 2.62-2.68 (2H, m), 3.42-3.45(4H, m), 6.94(1H, d, J = 8.9 Hz), 7.01-7.06 (2H, m), 7.18-7.23(2H, m), 7.76(2H, d, J = 8.2 Hz), 7.99-8.03 (3H, m), 8.22(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.28(1H, d, J = 2.6 Hz). 2539 3,4-Cl₂Ph— —CH₃ 4 1.50-1.80(4H, m), 2.32(3H, s), 2.38(2H, t, J = 7.3 Hz), 2.30-2.70(8H, m), 2.64(2H, t, J = 7.3 Hz), 6.94(1H, d, J = 8.8 Hz), 7.03(2H, d, J = 8.2 Hz), 7.19(2H, d, J = 8.2 Hz), 7.58(1H, d, J = 8.2 Hz), 7.72(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.84(1H, s), 8.00(1H, d, J = 2.0 Hz), 8.18(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.26 (1H, d, J = 2.6 Hz). 2540 3,4-Cl₂Ph— benzyl 4 1.45-1.75(4H, m), 2.36(2H, t, J = 7.5 Hz), 2.30- 2.65(8H, m), 2.62(2H, t, J = 7.7 Hz), 3.51(2H, s), 6.92(1H, d, J = 8.6 Hz), 7.03(2H, d, J = 8.6 Hz), 7.19(2H, d, J = 8.6 Hz), 7.15-7.40(5H, m), 7.57(1H, d, J = 8.2 Hz), 7.71(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.85(1H, s), 7.98(1H, d, J = 2.0 Hz), 8.16(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.24(1H, d, J = 2.5 Hz). 2541 3,4-Cl₂Ph— benzyl 5 1.25-1.45(2H, m), 1.45-1.75(4H, m), 2.34(2H, t, J = 7.7 Hz), 2.30-2.70(8H, m), 2.61(2H, t, J = 7.7 Hz), 3.51(2H, s), 6.93(1H, d, J = 8.7 Hz), 7.03(2H, d, J = 8.6 Hz) 7.19(2H, d, J = 8.6 Hz), 7.20-7.40(5H, m), 7.58(1H, d, J = 8.3 Hz), 7.70(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.71(1H, d, J = 2.0 Hz), 7.98(1H, d, J = 2.0 Hz), 8.16(1H, dd, J = 8.7 Hz 2.6 Hz) 8.24(1H, d, J = 2.6 Hz).

TABLE 398

Example No. R₁₁₀₆ R₁₁₀₇ Form ¹H NMR (DMSO-d₆) δppm 2542 3,4-Cl₂Ph— —H hydro- 1.12(3H, d, J = 6.3 Hz), 2.75-3.03(2H, chloride m), 3.24-3.39(2H, m), 3.78-3.98(3H, m), 4.31(2H, brs), 7.13(1H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.3 Hz), 7.63(2H, d, J = 8.3 Hz) 7.84(1H, d, J = 8.2 Hz), 7.98(1H, dd, J = 8.2 Hz, 2.6 Hz), 8.24(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.0 Hz), 8.55(1H, d, J = 2.6 Hz), 10.67(1H, brs), 11.10(1H, brs). 2543 3,4-Cl₂Ph— —O(CH₂)₃CH₃ hydro- 0.87(3H, t, J = 7.3 Hz), 1.22-1.36(2H, chloride m), 1.41-1.51(2H, m), 2.90-3.07(2H, m), 3.23-3.50(6H, m), 3.80-3.88(1H, m), 3.99-4.02(2H, m), 4.35(2H, brs), 7.13(1H, d, J = 8.9 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.63(2H, d, J = 8.3 Hz), 7.84(1H, d, J = 8.6 Hz), 7.97(1H, dd, J = 8.3 Hz 2.0 Hz), 8.24(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.0 Hz), 8.54(1H, d, J = 2.6 Hz), 10.66(1H, brs), 11.17(1H, brs). 2544 3,4-Cl₂Ph— piperidino dihydro- 1.38-1.77(6H, m), 2.92-3.10(5H, m), chloride 3.22-3.33(4H, m), 3.47-3.51(1H, m), 3.97-4.06(2H, m), 4.27-4.55(3H, m), 7.13 (1H, d, J = 8.9 Hz), 7.21(2H, d, J = 8.6 Hz), 7.67(2H, d, J = 8.6 Hz), 7.84(1H, d, J = 8.6 Hz), 7.99(1H, dd, J = 8.2 Hz, 2.0 Hz), 8.26(1H, dd, J = 8.6 Hz, 3.0 Hz), 8.28(1H, d, J = 2.3 Hz), 8.57(1H, d, J = 2.6 Hz), 10.27(1H, brs), 10.74(1H, brs), 11.91 (1H, brs). 2545 4-CF₃Ph— —H hydro- 1.12(3H, d, J = 6.1 Hz), 2.68-2.80(1H, chloride m), 2.98-3.06(1H, m), 3.24-3.28(2H, m), 3.80-3.90(3H, m), 4.31(2H, brs), 7.14(1H, d, J = 8.7 Hz), 7.21(2H, d, J = 8.4 Hz), 7 64(2H, d, J = 8.1 Hz), 7.93(2H, d, J = 8.4 Hz), 8.19(2H, d, J = 8.2 Hz), 8.27(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.57(1H, d, J = 2.6 Hz), 10.75(1H, brs), 11.19(1H, brs). 2546 4-CF₃Ph— —OCH₃ hydro- 2.92-3.12(2H, m), 3.26(3H, s), 3.34. chloride 3.47(4H, m), 3.80-4.02 (3H, m), 4.34(2H, brs), 7.14(1H, d, J = 8.9 Hz), 7.21(2H, d, J = 8.6 Hz), 7.63(2H, d, J = 8.2 Hz), 7.94(2H, d, J = 8.4 Hz), 8.18 (2H, d, J = 8.1 Hz), 8.27(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.57(1H, d, J = 2.6 Hz), 10.73(1H, brs), 11.13(1H, brs). 2547 3,4-Cl₂Ph— —OCH₃ hydro- 2.92-3.11(2H, m), 3.26(3H, s), 3.31- chloride 3.52(4H, m), 3.79-3.87 (1H, m), 3.95- 4.04(2H, m), 4.34(2H, brs), 714(1H, d, J = 8.9 Hz), 7.21(2H, d, J = 8.6 Hz), 7.62(2H, d, J = 8.6 Hz), 7.84(1H, d, J = 8.4 Hz), 7.97(1H, dd, J = 8.4 Hz, 2.2 Hz), 8.24-8.26(2H, m), 8.54(1H, d, J = 2.6 Hz), 10.66(1H, brs), 11.02(1H, brs).

TABLE 399

Example No. R₁₁₀₈ M Form ¹H NMR (solvent) δppm 2548

5 free (CDCl₃) 1.30-1.45(2H, m), 1.45-1.75(4H, m), 2.30(3H, s), 2.25-2.40 (2H, m), 2.49(8H, brs), 2.62(2H, t, J = 7.5 Hz), 6.94(1H, d, J = 8.9 Hz), 7.04(2H, d, J = 8.6 Hz), 7.20(2H, d, J = 8.6 Hz), 7.59(1H, d, J = 8.2 Hz), 7.65-7.75(2H, m), 7.98(1H, d, J = 2.0 Hz), 8.17(1H, dd, J = 8.9 Hz, 3.0 Hz), 8.24(1H, d, J = 3.0 Hz). 2549

1 hydro- chloride (DMSO-d₆) 1.13(6H, d, J = 6.6 Hz), 2.66-2.76(2H, m), 3.25-3.34 (2H, m), 3.91-3.99(2H, m), 4.30(2H, s), 7.14(1H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.62(2H, d, J = 8.3 Hz), 7.85(1H, d, J = 8.6 Hz), 7.97(1H, dd, J = 8.6 Hz, 2.0 Hz), 8.24(1H, dd, J = 8.6 Hz, 3.0 Hz), 8.25(1H, d, J = 2.3 Hz), 8.55(1H, d, J = 2.6 Hz), 10.65(1H, brs), 10.96(1H, brs). 2550

1 hydro- chloride (DMSO-d₆) 1.11(3H, d, J = 6.3 Hz), 1.40(3H, d, J = 6.9 Hz), 2.67-2.75(1H, m), 3.10(2H, m), 3.25- 3.33(1H, m), 4.02-4.32(4H, m), 7.14(1H, d, J = 8.9 Hz), 7.21(2H, d, J = 8.3 Hz), 7.65(2H, d, J = 8.6 Hz), 7.85(1H, d, J = 8.2 Hz), 7.97(1H, dd, J = 8.6 Hz, 2.0 Hz), 8.21-8.26(2H, m), 8.54(1H, d, J = 2.3 Hz), 10.46(1H, brs), 10.64(1H, brs).

Example 2551 Production of 1-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)-4-[2-(morpholino)acetyl]-piperazine

To a solution of 1-chloroacetyl-4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazine (0.515 g, 0.896 mmol) and diisopropylethylamine (0.234 ml, 1.34 mmol) in acetonitrile (11 mL) was added morpholine (0.117 mL, 1.34 mmol), and the resulting solution was refluxed for 1 hour. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and evaporated. The obtained solid was recrystallized from water-containing acetone, to thereby yield 0.441 g of the title compound.

Appearance: White powder

Melting point: 187-190° C.

The following compounds were produced in the same manner as in Example 2551.

TABLE 400

Example No. R₁₁₀₉ Form mp (° C.) or ¹H NMR 2552 —COCH₂N(C₂H₅)₂ 3/2 oxalate mp 107-118 2553 —COCH₂NHCH₂Ph hydrochloride mp 199-202 2554 —COCH₂N(C₂H₅)CH₂Ph fumarate ¹H NMR (DMSO-d₆) δ 0.99(3H, t, J = 7.1 Hz), 2.56-2.70(2H, m), 2.73- 2.86(2H, m), 3.09-3.50 (12H, m), 3.59(2H, s), 6.61(2H, s), 6.91(2H, d, J = 8.0 Hz), 6.98(2H, d, J = 9.0 Hz), 7.14-7.37(7H, m), 7.74(2H, d, J = 9.0 Hz), 7.81(1H, d, J = 8.4 Hz), 7.92(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.20(1H, d, J = 2.1 Hz), 10.39(1H, s), 13.09(2H, brs). 2555

dihydrochloride mp 173-176 2556 —COCH₂N(C₂H₅)Ph free mp 140-143

TABLE 401

Example No. R₁₁₁₀ mp (° C.) 2557

206-210 2558

154-156 2559 morpholino 177-178 2560

204-206 2561 —N(CH₃)CH₂Ph 182-184

TABLE 402

Example No. R₁₁₁₁ mp (° C.) 2562

151-152 2563 morpholino 177-178 2564

146-147

TABLE 403

Example No. R₁₁₁₂ mp (° C.) 2565 morpholino 195-197 2566

146-148 2567

173-176 2568

150-153

TABLE 404

Example No. R₁₁₁₃ Form mp (° C.) 2569

dihydrochloride 152-155 2570

dihydrochloride 181-185 2571 morpholino hydrochloride 146-150

TABLE 405

Example No. R₁₁₁₄ mp (° C.) 2572 morpholino 157-160 2573

241-243 2574

193-196 2575

180-182

TABLE 406

Example No. R₁₁₁₅ Xb₆₃ R₁₁₁₆ mp (° C.) or ¹H NMR 2576 3,4-Cl₂Ph— none morpholino ¹H NMR (DMSO-d₆ δ 2.50- 2.53 (4H, m), 3.55-3.61 (4H, m), 3.82 (2H, s), 7.20 (1H, d, J = 8.7 Hz), 7.21 (2H, d, J = 8.1 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.96 (1H, dd, J = 8.4 Hz, 1.2 Hz), 8.06 (2H, d, J = 8.4 Hz), 8.23 (1H, d, J = 1.5 Hz), 8.27 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.55 (1H, d, J = 2.8 Hz), 10.61 (1H, brs). 2577 4-CF₃Ph—

mp 179-181 2578 4-CF₃Ph—

mp 172-174 2579 4-CF₃Ph—

morpholino mp 144-146 2580 4-CF₃Ph—

—N(CH)CH₂Ph mp 188-190 2581 4-CF₃Ph—

mp 192-193

The following compound was produced in the same manner as in Reference Example 860.

Example 2582 1-{4-[5-(3,4-Dichlorobenzoylamino)pyridin-2-yloxy]benzyl}piperazine-4-carboxylic acid ethyl ester

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7.0 Hz), 1.76 (2H, m), 1.77 (2H, m), 2.03 (2H, t, J=11.5 Hz), 2.28 (1H, m), 2.87 (2H, brd, J=11.5 Hz), 3.48 (2H, s), 4.13 (2H, q, 7.0 Hz), 6.94 (1H, d, J=9.0 Hz), 7.06 (2H, d, J=8.5 Hz), 7.33 (2H, d, J=9.0 Hz), 7.57 (1H, d, J=8.5 Hz), 7.70 (1H, dd, J=8.5 Hz, 2.0 Hz), 7.88 (1H, brs), 7.97 (1H, d, J=2.0 Hz), 8.17 (1H, dd, J=9.0 Hz, 3.0 Hz), 8.24 (1H, d, J=3.0 Hz).

Example 2583 Production of 3,4-dichloro-N-{6-[4-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)phenoxy]pyridin-3-yl}benzamide

To uracil (200 mg, 1.8 mmol) was added hexamethyldisilazane (5 mL), and the resulting solution was stirred for 5.5 hours at 150′C. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a solution of acetonitrile (10 mL)-THF (5 mL), and to this solution were added 3,4-dichloro-N-[6-(4-chloromethylphenoxy)pyridin-3-yl]benzamide (500 mg, 1.2 mmol) and tin tetrachloride (3 drops). The resulting solution was refluxed for 2.5 hours. To this reaction solution was added methanol (1 mL), and the resulting solution was stirred for 30 minutes at room temperature. The resulting reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:chloroform=1:99→3:97), to thereby yield 20 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 4.88 (2H, s), 5.61 (1H, dd, J=7.9 Hz, 2.3 Hz), 7.07-7.13 (3H, m), 7.35 (2H, d, J=8.6 Hz), 7.79-7.85 (2H, m), 7.95 (1H, dd, J=8.6 Hz, 2.0 Hz), 8.18 (1H, d, J=2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.47 (1H, d, J=2.6 Hz), 10.55 (1H, s), 11.33 (1H, s);

MS: m/z 482 (M⁺).

Example 2584 Production of N-{6-[4-(4-benzyl-2-oxopiperazin-1-ylmethyl)phenoxy]pyridin-3-yl}-3,4-dichlorobenzamide dihydrochloride

To a solution of 4-benzylpiperazin-2-one (0.56 g, 2.95 mmol) in DMF (10 mL) was added 60% sodium hydride (0.12 g, 2.95 mmol), and this solution was stirred at room temperature for 30 minutes. 2-(4-chloromethylphenoxy)-5-nitropyridine (0.78 g, 2.95 mmol) was added to the reaction mixture, and the mixture was stirred for 1 hour at room temperature. To this mixture was added brine (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The remaining oil was dissolved in ethyl acetate (5 mL), and to the resulting solution was added iron powder (0.33 g, 5.89 mmol). This solution was stirred for 2 hours at room temperature. The resulting reaction solution was concentrated under reduced pressure, and a saturated sodium bicarbonate solution (50 mL) was added to the residue. The obtained mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The remaining oil was dissolved in THF (10 mL). To the resulting solution were added triethylamine (0.21 mL, 1.47 mmol) and 3,4-dichlorobenzoyl chloride (0.31 mL, 1.47 mmol), and this solution was stirred at room temperature for 2 hours. A saturated sodium bicarbonate solution (50 mL) was added to the solution, and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1). The obtained oil was dissolved in ethyl acetate (5 mL), and to the resulting solution was added a solution of 4 N hydrogen chloride in ethyl acetate (1.5 mL, 6 mmol). The formed white powder was collected by suction filtration, to thereby yield 0.045 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 3.54 (4H, m), 3.86 (2H, brs), 4.42 (2H, s), 4.59 (2H, brs), 7.06-7.12 (3H, m), 7.34 (2H, d, J=8.6 Hz), 7.48-7.51 (3H, m), 7.57-7.60 (2H, m), 7.84 (1H, d, J=8.6 Hz), 7.97 (1H, dd, J=2.0 Hz, 8.3 Hz), 8.18-8.24 (2H, m), 8.49 (1H, d, J=2.6 Hz), 10.61 (1H, s).

The following compound was produced in the same manner as in Reference Example 656.

Example 2585 2-({4-[(5-(3,4-Dichlorophenylamino)pyridin-2-yloxy]-2-trifluoromethylphenyl}ethylamino)-1-(4-piperonylpiperazin-1-yl)ethanone

¹H NMR (CDCl₃) δ 1.02 (3H, J=7.1 Hz), 2.30-2.45 (4H, m), 3.22 (2H, q, J=7.1 Hz), 3.40 (2H, s), 3.45-3.65 (4H, m), 3.85 (2H, s), 5.57 (1H, brs), 5.94 (2H, s), 6.65-6.80 (3H, m), 6.85 (1H, s), 6.95 (1H, d, J=8.7 Hz), 7.00 (1H, d, J=2.7 Hz), 7.29-7.31 (2H, m), 7.39 (1H, d, J=2.7 Hz), 7.53 (1H, dd, J=8.7 Hz, 2.9 Hz), 7.64 (1H, d, J=8.8 Hz), 7.99 (1H, d, J=2.7 Hz).

The following compounds were produced in the same manner as in Reference Example 658.

TABLE 407

Example No. R₁₁₁₇ R₁₁₁₈ M mp (° C.) or ¹H NMR (DMSO-d₆) δppm 2586 4-CF₃Ph— —H 2 ¹H NMR 2.14-2.30 (2H, m), 2.62-3.12 (7H, m), 3.20- 3.58 (3H, m), 3.77 (2H, t, J =5.9 Hz), 3.81-4.15 (3H, m), 4.16-4.32 (2H, m), 4.49-4.57 (1H, m), 6.08 (2H, a), 6.96-7.09 (5H, m), 7.21 (1H, s), 7.29 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.70 (2H, d, J = 8.8 Hz), 7.86 (1H, dd, J = 2.8 Hz, 8.8 Hz, 8.13 (1H, d, J = 2.8 Hz), 10.78-11.01 (1H, m). 2587 3,4-Cl₂Ph— —H 2 mp 182.0-183.0 2588 3-CF₃Ph— —H 1 mp 200.0-203.0 2589 4-CF₃Ph— —OCH₃ 1 mp 153.0-154.0 2590 3,4-Cl₂Ph— —OCH₃ 1 mp 169.0-171.0 2591 4-CF₃Ph— —OCH₃ 2 mp 134.0-136.0 2592 3,4-Cl₂Ph— —OCH₃ 2 mp 130.0-132.0

TABLE 408

Example No. R₁₁₁₉ M mp (° C.) or ¹H NMR (DMSO-d₆) δppm 2593 4-CF₃Ph— 1 ¹H NMR 1.90-2.06 (2H, m), 2.07 (3H, s), 3.18-3.32 (2H, m), 3.55-3.70 (2H, m), 3.73 (3H, s), 3.74 (3H, s), 3.91-4.12 (4H, m), 4.43 (2H, s), 4.49-4.93 (1H, m), 6.81 (1H, dd, J = 1.8 Hz, 8.1 Hz), 6.88 (1H, d, J = 1.8 Hz), 6.92 (1H, d, J = 8.1 Hz), 6.97 (1H, d, J = 8.5 Hz), 7.06 (1H, d, J = 9.0 Hz), 7.12 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.21 (1H, d, J = 2.4 Hz), 7.71 (2H, d, J = 8.9 Hz), 7.83 (2H, d, J = 8.9 Hz), 8.19 (1H, dd, J = 2.9 Hz, 9.0 Hz), 8.27 (1H, d, J = 2.9 Hz). 2594 3,4-Cl₂Ph— 1 mp 146.0-148.0 2595 3,4-Cl₂Ph— 2 ¹H NMR 1.91-2.11 (5H, m), 2.12-2.24 (2H, m), 3.19-3.32 (2H, m), 3.58-3.83 (10H, m), 3.85-4.22 (3H, m), 4.42 (2H, s), 6.81 (1H, dd, J = 1.8 Hz, 8.1 Hz), 6.87 (1H, d, J = 1.8 Hz), 6.91 (1H, d, J = 8.1 Hz), 6.94-7.02 (2H, m), 7.12 (1H, dd, J = 2.5 Hz, 8.6 Hz), 7.21 (1H, d, J = 2.5 Hz), 7.35 (1H, dd, J = 2.5 Hz, 8.8 Hz), 7.57 (1H, d, J = 8.8 Hz), 7.66 (1H, d, J = 2.5 Hz), 7.82 (1H, dd J = 2.5 Hz 8.8 Hz), 8.07 (1H d J = 2.5 Hz).

Example 2596 Production of 3-(4-{5-[4-(3,4-dichlorophenyl)piperazin-1-yl]pyridin-2-yloxy}phenyl)-1-(4-piperonylpiperazin-1-yl)propane-1-one

To a solution of 3-[4-(5-bromopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (359 mg, 0.69 mmol) and 1-(3,4-dichlorophenyl)piperazine (206 mg, 0.89 mmol) in toluene (16 mL) were added with Pd₂(dba)₃ (25 mg, 0.027 mmol), Xantphos (32 mg, 0.055 mmol) and sodium t-butoxide (99 mg, 1.03 mmol), and the resulting solution was refluxed under an argon atmosphere for 3 hours. The solution was left to cool, water was added to this reaction mixture. The resulting solution was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), to thereby yield 236 mg of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 2.31-2.40 (4H, m), 2.58-2.64 (2H, m), 2.92-2.98 (2H, m), 3.23-3.38 (8H, m), 3.41 (4H, brs), 3.63 (2H, t, J=4.9 Hz), 5.94 (2H, s), 6.72-6.73 (2H, m), 6.78 (1H, dd, J=8.9 Hz, 2.8 Hz), 6.84-6.90 (2H, m), 6.99-7.06 (3H, m), 7.19-7.24 (3H, m), 7.32 (1H, dd, J=9.4 Hz, 3.1 Hz), 7.88 (1H, d, J=3.0 Hz). Tris(dibenzylideneacetone)dipalladium is abbreviated to Pd₂(dba)₃. Hereinafter, the same. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene is abbreviated to Xantphos. Hereinafter the same.

The following compounds were produced in the same manner as in Example 2596.

TABLE 409

Example No. R₁₁₂₀ R₁₁₂₁ Xb₆₄ ¹H NMR (CDCl₃) δppm 2597 4-CF₃PhCH₂— —H —CH₂— 2.31-2.38 (4H, m), 2.60-2.64 (6H, m), 2.95 (2H, t, J = 7.3 Hz), 3.11-3.15 (4H, m), 3.40 (4H, brs), 3.61 (4H, brs), 5.93 (2H, s), 6.73 (2H, s), 6.83 (2H, d, J = 9.1 Hz), 6.99 (2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.29 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.47 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.1 Hz), 7.83 (1H, d, J = 3.0 Hz). 2598 3,4-Cl₂Ph— —CH₃ —N(CH₃)— 2.13 (3H, s), 2.40-2.44 (4H, m), 3.00 (3H, s), 3.18- 3.38 (8H, m), 3.43 (2H, s), 3.49 (2H, brs), 3.63 (2H, brs), 4.06 (2H, s), 5.94 (2H, s), 6.52-6.57 (2H, m), 6.69-6.91 (6H, m), 7.00 (1H, d, J = 3.0 Hz), 7.26- 7.32 (2H, m), 7.86 (1H, d, J = 2.8 Hz). 2599 4-CF₃Ph— —CH₃ —N(CH₃)— 2.13 (3H, s), 2.41-2.44 (4H, m), 3.00 (3H, s), 3.20- 3.24 (4H, m), 3.34-3.43 (6H, m), 3.49 (2H, brs), 3.63 (2H, brs), 4.06 (2H, s), 5.94 (2H, s), 6.52- 6.58 (2H, m), 6.70-6.77 (3H, m), 6,85-6.98 (4H, m), 7.31 (1H, dd, J = 9.1 Hz, 3.1 Hz), 7.50 (2H, d, J = 8.6 Hz), 7.87 (1H, d, J = 2.6 Hz). 2600 4-CF₃Ph— —H —CH₂— 2.31-2.40 (4H, m), 2.61 (2H, t, J = 7.3 Hz), 2.96 (2H, t, J = 7.3 Hz), 3,23-3.27 (4H, m), 3.38- 3.45 (8H, m), 3.63 (2H, t, J = 4.8 Hz), 5.94 (2H, s), 6.70-6.76 (2H. m), 6.84-7.06 (6H, m), 7.19- 7.26 (2H, m), 7.36 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.51 (2H, d, J = 8,9 Hz), 7.89 (1H, d. J = 3.0 Hz).

The following compounds were produced in the same manner as in Reference Example 659.

TABLE 410

Example No. R₁₁₂₂ Xb₆₅ Xb₆₆ R₁₁₂₃ ¹H NMR (CDCl₃) δppm 2601 4-CF₃Ph— —N(CH₃)— —CH₂— piperonyl 2.41-2.44 (4H, m), 3.03 (3H, s), 3.43 (2H, s), 3.47-3.50 (2H, m), 3.61-3.65 (2H, m), 4.09 (2H, s), 5.93 (2H, s), 6.68-6.77 (4H, m), 6.83-6.86 (2H, m), 6.90 (1H, d, J = 16.5 Hz), 7.00-7.06 (2H, m), 7.10 (1H, d, J = 16.5 Hz), 7.54-7.61 (4H, m), 7.84 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.26 (1H, d, J = 2.5 Hz). 2602 3,4-Cl₂Ph— —N(CH₃)— —CH₂— piperonyl 2.42-2.45 (4H, m), 3.04 (3H, s), 3.44 (2H, s), 3.48-3.52 (2H, m), 3.62-3.66 (2H, m), 4.09 (2H, s), 5.95 (2H, s), 6.68-6.86 (6H, m), 6.94 (1H, d, J = 17.3 Hz), 6.99- 7.04 (3H, m), 7.31 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.42 (1H, d. J = 8.4 Hz), 7.57 (1H, d, J = 2.0 Hz), 7.82 (1H, d, J = 8.4 Hz), 8.24 (1H, brs). 2603 4-CF₃Ph— —CH₂— —CH₂— piperonyl 2.32-2.41 (4H, m), 2.60-2.66 (2H, m), 2.96-3.01 (2H, m), 3.39-3.43 (4H, m), 3.62-3.66 (2H, m), 5.95 (2H, s), 6.70- 6.77 (2H, m), 6.84-6.85 (1H, m), 6.93 (1H, d, J = 8.6 Hz), 7.00-7.09 (3H, m), 7.12 (1H, d, J = 16.5 Hz), 7.23-7.27 (2H, m), 7.56-7.64 (4H, m), 7.90 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.27 (1H, d, J = 2.6 Hz). 2604 4-CF₃Ph— none none benzyl 2.47 (4H, brs), 3.55-3.77 (6H, m), 6.97 (1H, d, J = 8.6 Hz), 7.05 (1H, d, J = 16.3 Hz), 7.10-7.27 (3H, m), 7.28- 7.34 (5H, m), 7.45-7.50 (2H, m), 7.57- 7.64 (4H, m), 7.93 (1H, dd, J = 8.6 Hz, 2.4 Hz), 8.29 (1H, d, J = 2.4 Hz). 2605 3,4-Cl₂Ph— none none benzyl 2.52 (4H, brs), 3.49-3.90 (6H, m), 6.89- 6.98 (2H, m), 7.03 (1H, d, J = 16.5 Hz), 7.15-7.20 (2H, m), 7.30-7.50 (9H, m), 7.58 (1H, d, J = 2.1 Hz), 7.90 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.26 (1H, d, J = 2.5 Hz).

TABLE 411

Example No. R₁₁₂₄ Form ¹H NMR (solvent) δppm 2606 piperonyl hydrobromide (DMSO-d₆) 1.89-2.06 (2H, m), 2.06 (3H, s), 3.18-3.35 (2H, m), 3.57-3.71 (2H, m), 4.40 (2H, s), 4.42-4.80 (1H, m, 5.99 (2H, s), 6.77 (1H, dd, J = 1.6 Hz, 7.9 Hz), 6.84 (1H, d, J = 1.6 Hz), 6.87 (1H, d, J = 7.9 Hz), 7.01 (1H, d, J = 8.6 Hz), 7.07 (1H, d, J = 8.6 Hz), 7.13 (1H, dd, J = 2.5 Hz, 8.6 Hz), 7.23 (1H, d, J = 2.5 Hz), 7.32 (1H, d, J = 16.5 Hz), 7.42 (1H, d, J = 16.5 Hz), 7.72 (2H, d, J = 8.5 Hz), 7.79 (2H, d, J = 8.5 Hz), 8.19 (1H, dd, J = 2.4 Hz, 8.6 Hz), 8.30 (1H, d, J = 2.4 Hz). 2607 3,4- free (CDCl₃) 1.99-2.14 (2H, m), 2.18 (3H, s), 3.22- (CH₃O)₂PhCH₂— 3.38 (2H, m), 3.63-3.79 (2H, m), 3.89 (3H, s), 3.90 (3H, s), 4.57 (2H, s), 6.76-6.95 (4H, m), 6.97-7.20 (4H, m), 7.51-7.67 (4H, m), 7.88 (1H, dd, J = 2.5 Hz, 8.6 Hz), 8.27 (1H, d, J = 2.5 Hz).

Example 2608 Production of 1-(3,4-dimethoxybenzyl)-3-{3-methyl-4-[5-(4-trifluoromethylphenylethynyl)pyridin-2-yloxy]phenyl}tetrahydropyrimidin-2-one

To a solution of 1-[4-(5-bromopyridin-2-yloxy)-3-methylphenyl]-3-(3,4-dimethoxybenzyl)tetrahydropyrimidin-2-one (0.3 g, 0.59 mmol) in N-methylpyrrolidone (10 mL) were added bis(triphenylphosphine)palladium dichloride (20 mg, 0.03 mmol), copper iodide (11 mg, 0.059 mmol), 4-ethynyl-α,α,α-trifluorotoluene (0.14 mL, 0.88 mmol) and triethylamine (0.14 mL, 10 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 3 hours at 110 to 120° C. After being left to cool, water was added to the reaction solution. The resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1→1:1), to thereby yield 0.28 g of the title compound.

Appearance: Pale brown amorphous powder

¹H NMR (CDCl₃) δ 1.97-2.15 (2H, m), 2.16 (3H, s), 3.31 (2H, t, J=6.0 Hz), 3.72 (2H, t, J=6.0 Hz), 3.88 (3H, s), 3.89 (3H, s), 4.57 (2H, s), 6.72-6.95 (5H, m), 7.04 (1H, d, J=8.6 Hz), 7.17 (1H, dd, J=2.6 Hz, 8.6 Hz), 7.55-7.68 (4H, m), 7.78 (1H, dd, J=2.3 Hz, 8.6 Hz), 8.36 (1H, d, J=2.3 Hz).

Example 2609 Production of 3-(3-methyl-4-{5-[2-oxo-2-(4-trifluoromethylphenyl)ethyl]pyridin-2-yloxy}phenyl)-1-piperonyltetrahydropyrimidin-2-one hydrobromide

To a solution of 3-[4-(5-bromopyridin-2-yloxy)-3-methylphenyl]-1-piperonyltetrahydropyrimidin-2-one (0.11 g, 0.22 mmol) in toluene (10 mL) were added Pd₂(dba)₃ (10 mg, 0.01 mmol) and Xantphos (15 mg, 0.03 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 5 minutes, and then 4′-(trifluoromethyl)acetophenone (63 mg, 0.33 mmol) and potassium bis(trimethylsilyl)amide (66 mg, 0.33 mmol) were added to the reaction solution. The resulting solution was stirred at 70 to 80° C. for 30 minutes, and left to cool. Water was added to the reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1), to yield 50 mg of a free form. To this free form was added an equivalent amount of hydrobromic acid, to thereby yield 50 mg of the title compound.

Appearance: Colorless amorphous powder

¹H NMR (DMSO-d₆) δ 1.85-2.10 (2H, m), 2.06 (3H, s), 3.14-3.47 (2H, m), 3.50-3.76 (2H, m), 4.40 (2H, s), 4.49 (2H, s), 4.70-5.40 (1H, m), 5.98 (2H, s), 6.70-6.80 (1H, m), 6.81-6.90 (2H, m), 6.90-7.04 (2H, m), 7.12 (1H, d, J=2.2 Hz, 8.6 Hz), 7.18-7.26 (1H, m), 7.72 (1H, dd, J=2.2 Hz, 8.5 Hz), 7.93 (2H, d, J=8.2 Hz), 7.95-8.02 (1H, m), 8.24 (2H, d, J=8.2 Hz).

The following compounds were produced in the same manner as in Example 2609.

TABLE 412

Example No. R₁₁₂₅ R₁₁₂₆ ¹H NMR (CDCl₃) δppm 2610 3,4-Cl₂Ph— piperonyl 1.82-2.10 (2H, m), 2.07 (3H, s), 3.12-3.32 (2H, m), 3.53-3.72 (2H, m), 4.40 (2H, s), 4.45 (2H, s), 4.80- 5.40 (1H, m), 5.99 (2H, s), 6.71-6.80 (1H, m), 6.81- 6.90 (2H, m), 6.98 (2H, dd, J = 2.4 Hz, 8.5 Hz), 7.12 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.21 (1H, d, J = 2.4 Hz), 7.70 (1H, dd, J = 2.2 Hz, 8.4 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.96 (1H, d, J = 2.2 Hz), 8.00 (1H, dd, J = 2.0 Hz, 8.4 Hz), 8.25 (1H, d, J = 2.0 Hz). 2611 4-CF₃Ph— 3,4-(CH₃O)₂Ph— 1.87-2.11 (5H, m), 3.15-3.32 (2H, m), 3.43-3.71 (3H, m), 3.74 (3H, s), 3.75 (3H, s), 4.44 (2H, s), 4.51 (2H, s), 6.78-6.86 (1H, m), 6.87-6.91 (1H, m), 6.93 (1H, d, J = 8.5 Hz), 6.99 (1H, d, J = 8.5 Hz), 7.00 (1H, d, J = 8.5 Hz), 7.14 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.19-7.25 (1H, m), 7.73 (1H, dd J = 2.4 Hz, 8.5 Hz), 7.94 (1H, d, J = 8.3 Hz), 7.97-8.01 (1H, m), 8.25 (1H, d, J = 8.3 Hz).

TABLE 413

Example No. R₁₁₂₇ mp (° C.) or ¹H NMR (solvent) δppm 2612

¹H NMR (CDCl₃) 2.44 (4H, brs), 3.44 (2H, s), 3.54 (2H, brs), 3.73 (2H, brs), 4.29 (2H, s), 5.94 (2H, s), 6.74 (2H, s), 6.85 (1H, s), 6.94 (1H, d, J = 8.4 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.6 Hz), 7.63 (1H, dd, J = 8.4 Hz, 2.5 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.07 (1H, d, J = 2.5 Hz), 8.11 (2H, d, J = 8.1 Hz). 2613

¹H NMR (DMSO-d₆) 2.31 (3H, s), 2.76- 3.45 (9H, m), 3.69-4.57 (8H, m), 6.07 (2H, s), 6.81-7.22 (6H, m), 7.74 (1H, dd, J = 2.2 Hz, 8.4 Hz), 7.89-8.00 (2H, m), 8.24 (1H, d, J = 8.4 Hz), 9.49-9.79 (1H, m). 2614

mp 164.0-166.0

The following compounds were produced in the same manner as in Reference Example 111.

TABLE 414

Example No. Xb₆₇ ¹H NMR (solvent) δppm 2615 —N(CH₃)— 2.42-2.45 (4H, m), 3.05 (3H, s), 3.44 (2H, s), 3.47-3.51 (2H, m), 3.62- 3.65 (2H, m), 4.11 (2H, s), 5.95 (2H, s), 6.69-6.77 (4H, m), 6.85 (1H, s), 6.97 (1H, d, J = 8.7 Hz), 7.01-7.07 (2H, m), 7.75 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.1. Hz), 8.17 (1H, dd, J = 8.7 Hz, 2.3 Hz), 8.58 (1H, d, J = 2.3 Hz). 2616 —CH₂— 2.32-2.41 (4H, m), 2.61-2.67 (2H, m), 2.97-3.03 (2H, m), 3.41- 3.43 (4H, m), 3.62-3.66 (2H, m), 5.95 (2H, s), 6.70-6.77 (2H, m), 6.84 (1H, s), 7.03-7.13 (3H, m), 7.28-7.32 (2H, m), 7.76 (2H, d, J = 8.1 Hz), 7.88 (2H, d, J = 8.1 Hz), 8.22 (1H, dd, J = 8.6 Hz, 2.4 Hz), 8.58 (1H, d, J = 2.4 Hz).

TABLE 415

Example No. R₁₁₂₈ R₁₁₂₉ ¹H NMR CDCl₃) δppm 2617 —H —CH₂COOC₂H₅ 1.27 (3H, t, J = 7.1 Hz), 1.34-1.48 (2H, m), 1.81-1.99 (3H, m), 2.29 (2H, d, J = 6.9 Hz), 2.73 (2H, t, J = 12.2 Hz), 3.63 (2H, d, J = 12.2 Hz), 4.15 (2H, q, J =7.3 Hz), 6.91- 7.01 (4H, m), 7.18-7.26 (3H, m), 7.54 (2H, d, J = 8.9 Hz), 8.26 (1H, d, J = 2.3 Hz), 8.43 (1H, d, J = 2.3 Hz). 2618 —CH₃ —CH₂COOC₂H₅ 1.28 (3H, t, J = 7.1 Hz), 1.30-1.39 (2H, m), 1.80-1.96 (3H, m), 2.07 (3H, s), 2.29 (2H, d, J = 6.9 Hz), 2.70 (2H, t, J = 12.0 Hz), 3.61 (2H d, J = 12.4 Hz), 4.17 (2H, q, J = 7.3 Hz), 6.74-6.78 (2H, m), 6.92 (1H, d, J = 8.6 Hz), 7.20- 7.26 (3H, m), 7.52 (2H, d, J = 8.4 Hz), 8.28 (1H, d, J = 2.3 Hz), 8.41 (1H, d, J = 2.3 Hz). 2619 —H —COOC₂H₅ 1.27 (3H, t, J = 7.1 Hz), 1.92-2.00 (2H, m), 2.01-2.05 (2H, m), 2.38-2.47 (1H, m), 2.74-2.84 (2H, m), 3.59-3.63 (2H, m), 4.15 (2H, q, J = 7.1 Hz), 6.93-7.02 (4H, m), 7.17- 7.26 (3H, m), 7.54 (2H, d, J = 8.4 Hz), 8.26 (1H, d, J = 2.3 Hz), 8.43 (1H, d, J = 2.3 Hz).

TABLE 416

Example No. R₁₁₃₀ R₁₁₃₁ mp (° C.) or ¹H NMR (DMSO-d₆) δppm 2620 4-CF₃Ph— piperonyl mp 129.0-130.5 2621 4-CF₃Ph— 3,4-(CH₃O)₂PhCH₂— mp 130.0-132.0 2622 3,4-Cl₂Ph— 3,4-(CH₃O)₂PhCH₂— ¹H NMR 1.85-2.14 (5H, m), 3.13-3.33 (2H, m), 3.58-3.71 (2H, m), 3.73 (3H, s), 3.74 (3H, s), 4.12-4.78 (3H, m), 6.73-6.94 (3H, m), 7.04 (1H, d, J = 8.6 Hz), 7.11-7.20 (2H, m), 7.25 (1H, d, J = 2.4 Hz), 7.61 (1H, d, J = 8.8 Hz), 7.71 (1H, dd, J = 2.4 Hz, 8.8 Hz), 8.11 (1H, d, J = 2.4 Hz), 8.34 (1H, dd J = 2.4 Hz, 8.8 Hz), 8.66 (1H, d, J = 2.4 Hz), 10.53 (1H, s).

Example 2623 Production of 2-[4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazin-1-yl]acetic acid hydrochloride

To a solution of ethyl 2-[4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazin-1-yl]acetate (0.493 g, 0.843 mmol) in THF (5 mL) and ethanol (5 mL) were added 5 M aqueous sodium hydroxide (0.253 mL, 1.27 mmol) and water (1 mL), and the resulting solution was refluxed for 1 hour. This reaction solution was concentrated under reduced pressure, and the residue was dissolved in 50% aqueous ethanol. To the resulting solution was added 5 M hydrochloric acid (0.253 mL, 1.27 mmol), and the obtained solid was collected by filtration. To this solid was dissolved in ethanol (10 mL) and 5 M hydrochloric acid (0.3 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from ethanol-diethyl ether, to thereby yield 0.381 g of the title compound.

Appearance: White powder

Melting point: 215-218° C.

The following compounds were produced in the same manner as in Example 2623.

TABLE 417

Ex- ample No R₁₁₃₂ ¹H NMR (solvent) δppm 2624

(DMSO-d₆) 2.71-2.73(4H, m), 3.12-3.14(4H, m), 3.21(2H, s), 6.91-6.98 (6H, m), 7.71(2H, dd, J = 7.0 Hz, 2.0 Hz), 7.82(1H, d, J = 8.0 Hz), 7.93(1H, dd, J = 8.0 Hz, 2.0 Hz), 8.21(1H, d, J = 2.0 Hz), 10.38(1H, s). 2625

(CDCl₃) 2.68(2H, m), 3.05(2H, m), 3.35(2H, s), 3.49(2H, m), 6.00(1H, m), 6.98(2H, d, J = 8.5 Hz), 7.05(2H, d, J = 8.5 Hz), 7.35(2H, d, J = 8.5 Hz), 7.58(2H, d, J = 8.5 Hz), 7.58(1H, brs), 7.77(2H, m), 7.97(1H, s). 2626

DMSO-d₆)7.60-1.70(2H, m), 1.85-1.90(2H, m), 2.50(1H, m), 2.65-2.73(2H, m), 3.55(2H, brd, J = 12.5 Hz), 6.90-6.98(6H, m), 7.71(2H, d, J = 9.0 Hz), 7.81(1H, d, J = 8.5 Hz), 7.93(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1H, d, J = 2.0 Hz), 10.37(1H, s), 12.20(1H, brs). 2627

(DMSO-d₆) 1.51-1.58(2H, m), 1.90-1.95(2H, m), 2.78-2.82(2H, m), 3.43(2H, m), 3.52(1H, m), 3.92(2H, s), 6.89-6.98(6H, m), 7.70(2H, d, J = 9.0 Hz), 7.82(1H, d, J = 8.5 Hz), 7.93(1H, dd, J = 8.5 Hz, 2.0 Hz) 8.21(1H, d, J = 2.0 Hz), 10.40(1H, s). 2628

(DMSO-d₆) 1.59-1.66(2H, m), 1.94-1.97(2H, m), 2.54(3H, s), 3.62(2H, t, J = 11.0 Hz), 2.98(1H, m), 3.29(2H, s), 3.67- 3.70(2H, m), 6.90-6.99(6H, m), 7.71(2H, d, J = 9.0 Hz), 7.82(1H, d, J = 8.5 Hz), 7.93(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1H, d, J = 2.0 Hz), 10.39(1H, s). 2629

(CDCl₃) 1.80-1.83(4H, m), 2.61-2.65(3H, m), 3.24(2H, s), 3.25(2H, brd, J = 11.0 Hz), 6.94(2H, d, J = 8.5 Hz), 7.03(2H, d, J = 9.0 Hz), 7.25(2H, d, J = 8.5 Hz), 7.03(2H, Hz), 7.83(1H, d, J = 8.5 Hz), 7.94(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1H, d, J = 2.0 Hz), 10.41(1H, s).

TABLE 418

Ex- ample No R₁₁₃₃ Xb₆₈ Xb₆₉ M ¹H NMR (DMSO-d₆) δppm 2630 4-CF₃Ph— —N(CH₃)— none 1 1.20-1.45(2H, m), 1.70-1.95(3H, m), 2.20(2H, d, J = 6.6 Hz), 2.67(2H, t, J = 12.4 Hz), 3.32(3H, s), 3.67(2H, d, J = 12.4 Hz), 6.42(1H, d, J = 9.1 Hz), 6.99(2H, d, J = 8.9 Hz), 7.11(2H, d, J = 8.9 Hz), 7.73(1H, dd, J = 9.1 Hz, 2.3 Hz), 7.90(2H, d, J = 8.2 Hz), 8.15(2H, d, J = 8.2 Hz), 8.46(1H, d, J = 2.3 Hz), 10.33(1H, s). 2631 3,4-Cl₂Ph— —O— —CH₂— 0 1.57(2H, brs), 1.81(2H, brs), 2.00(2H, brs), 2.23(1H, brs), 2.77(2H, brs), 3.44(2H, brs), 7.05(1H, d, J = 9.0 Hz), 7.07(2H, d, J = 8.5 Hz), 7.35(2H, d, J = 8.5 Hz), 7.84(1H, d, J = 8.5 Hz), 7.95(1H, d, J = 8.5 Hz), 8.20 (1H, dd, J = 9.0 Hz, 3.0 Hz), 8.22(1H, d, J = 2.0 Hz), 8.49(1H, d, J = 3.0 Hz), 10.56(1H, s), 12.15(1H, brs). 2632 3,4-Cl₂Ph— —O— —CO— 0 1.52(2H, m), 1.86(2H, brs), 2.52(1H, m), 3.10(2H, brs), 3.65(1H, brs), 4.31(1H, brs), 7.15(1H, d, J = 9.0 Hz), 7.16(2H, d, J = 8.5 Hz), 7.43(2H, d, J = 8.5 Hz), 7.84(2H, d, J = 8.5 Hz), 7.95(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.23(1H, d, J = 2.0 Hz), 8.24(1H, dd, J = 9.0 Hz, 3.0 Hz), 8.52(1H, d, J =3.0 Hz), 10.60(1H, s). 2633 4-CF₃Ph— —O— —CO— 0 1.52(2H, m), 1.86(2H, brs), 2.54(1H, m), 3.05(2H, brs), 3.63(1H, brs), 4.31(1H, brs), 7.15(1H, d, J = 9.0 Hz), 7.16(2H, d, J = 8.5 Hz), 7.44(2H, d, J = 8.5 Hz), 7.94 (2H, d, J = 8.5 Hz), 8.17(2H, d, J = 8.5 Hz), 8.27(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.55(1H, d, J = 2.5 Hz), 10.67(1H, s). 2634 3,4-Cl₂Ph— —O— none 0 1.63-1.71(2H, m), 1.92(2H, brd, J = 10.0 Hz), 2.74(2H, t, J = 11.5 Hz), 3.58(2H, brd, J = 12.5 Hz), 6.96(1H, d, J = 9.0 Hz), 6.98(4H, s), 7.83(1H, d, J = 8.5 Hz), 7.94(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.14(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.21(1H, d, J = 2.0 Hz), 8.44(1H, d, J = 2.5 Hz), 10.50(1H, s), 12.20(1H, brs). 2635 3,4-Cl₂Ph— —O— none 1 1.31-1.34(2H, m), 1.77(2H, brd, J = 11.5 Hz), 2.20(2H, t, J = 6.5 Hz), 2.64(2H, brt, J = 10.5 Hz), 3.61(2H, brd, J =12.5 Hz), 6.96(1H, J = 9.0 Hz), 6.96(4H, s), 7.83 (1H, d, J = 8.5 Hz), 7.94(1H, dd, J = 8.5 Hz, 2.0 Hz), 8,14(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.21(1H, d, J = 2.0 Hz), 8.44(1H, d, J = 2.5 Hz), 10.50(1H, s), 12.06(1H, brs).

TABLE 419

Ex- ample No. R₁₁₃₄ Xb₇₀ Xb₇₁ Xb₇₂ ¹H NMR (DMSO-d₆) δppm 2636 4-CF₃Ph— —O— —CO— —CH₂— 3.30(4H, brs), 3.77(4H, brs), 3.99(2H, s), 7.17(1H, d, J = 8.8 Hz), 7.21(2H, d, J = 8.6 Hz), 7.51(2H, d, J = 8.6 Hz), 7.94(2H, d, J = 8.0 Hz), 8.20(2H, d, J = 8.0 Hz), 8.29(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.59(1H, d, J = 2.6 Hz), 10.79(1H, s). 2637 3,4-Cl₂Ph— —O— none —CH₂— 2.71(4H, t, J = 5.0 Hz), 3.13(2H, s), 3.14(4H, t, J = 5.0 Hz), 6.96-7.00(5H, m), 7.82(1H, d, J = 8.5 Hz), 7.96(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.16(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.24(1H, d, J = 2.0 Hz), 8.37(1H, s), 8.46(1H, d, J = 2.5 Hz), 10.62(1H, brs). 2638 4-CF₃Ph— —N(CH₃)— none —CH₂— 2.64(4H, brs), 2.95(2H, s), 3.15(4H, brs), 3.33(3H, s), 6.42(1H, d, J = 9.1 Hz), 6.99(2H, d, J = 8.9 Hz), 7.13(2H, d, J = 8.9 Hz), 7.75(1H, dd, J = 9.1 Hz, 2.5 Hz), 7.89(2H, d, J = 8.2 Hz), 8.17(2H, d, J = 8.2 Hz), 8.49(1H, d, J = 2.5 Hz), 10.46(1H, s). 2639 4-CF₃Ph— —O— none —CH₂— 2.72(4H, t, 3 = 5.0 Hz), 3.15(4H, t, J = 5.0 Hz), 3.20(2H, s), 6.96-7.01(5H, m), 7.93(2H, d, J = 8.5 Hz), 8.16(2H, d, J = 8.5 Hz), 8.18(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.46(1H, d, J = 2.5 Hz), 10.60(1H, s). 2640 3,4-Cl₂Ph— —O— none —CO— 3.13(2H, brs), 3.17(2H, s), 3.48(2H, brs), 3.71(2H, brs), 7.12(1H, d, J = 8.9 Hz), 7.15(2H, dd, J = 6.8 Hz, 2.1 Hz), 7.36(2H, dd, J = 6.8 Hz, 2.1 Hz), 7.84(1H, d, J = 8.4 Hz), 7.95(1H, dd, 3 Hz, 2.7 Hz), 8.23(1H, d, J = 2.1 Hz), 8.49 (1H, d, 3 = 2.7 Hz), 10.58(1H, s).

TABLE 420

Ex- ample ¹H NMR (solvent) No R₁₁₃₅ Xb₇₃ Xb₇₄ Xb₇₅ R₁₁₃₆ δppm 2641 4-CF₃PhCO— none none none benzyl (CD₃OD) 3.47(8H, brs), 4.43(2H, s), 6.96 (1H, d, J = 8.9 Hz), 7.14(1H, d, J = 8.9 Hz), 7.30(1H, dd, J = 8.9 Hz, 3.0 Hz), 7.51- 7.59(6H, m), 7.82(2H, d, J = 8.3 Hz), 8.12- 8.18(3H, m), 8.36(1H, d, J = 2.5 Hz). 2642 3,4-Cl₂PhSO₂— —N(C₂H₅)— —CH₂— —CO— piperonyl (DMSO-d₆) 1.11(3H, t, J = 7.0 Hz), 2.20-2.45 (4H, m), 3.30-3.55(8H, m), 4.22(2H, s), 5.99 (2H, s), 6.70-7.00(7H, m) 7.40-7.50(1H, m), 7.55-7.60(1H, m), 7.66(1H, d, J = 2.7 Hz), 7.84(1H, d, J 8.4 Hz), 7.88(1H, d, J = 2.1 Hz), 10.27(1H, brs), 12.51(1H, brs). 2643 3,4-Cl₂PhNHCO— —N(C₂H₅)— —CH₂— —CO— piperonyl (DMSO-d₆) 1.13(3H, t, J = 7.0 Hz), 2.20-2.50 (4H, m), 3.30-3.60(8H, m), 4.21(2H, s), 5.99 (2H, s), 6.60-7.05(7H, m) 7.30-7.40(1H, m) 7.47(1H, Hz), 7.65-7.85(1H, m), 7.90(1H, d, J = 2.3 Hz), 8.06(1H, d, J = 2.6 Hz), 9.80(2H, brs), 12.40(1H, brs).

TABLE 421

Ex- ample No. R₁₁₃₇ R₁₁₃₈ R₁₁₃₉ R₁₁₄₀ ¹H NMR (solvent) δppm 2644 3,4-Cl₂Ph— —H —H —COOH (CDCl₃) 1.80(1H, m), 1.86-1.94(3H, m), 2.82(1H, m), 3.14(2H, m), 3.32 (2H, m), 6.94(1H, d, J = 9.0 Hz), 7.06(4H, s), 7.57(1H, d, J = 8.5 Hz), 7.72(1H, d, J = 8.5 Hz), 7.93(1H, brs), 7.99(1H, s), 8.18(1H, brd, J = 9.0 Hz), 8.26(1H, d, J = 2.5 Hz). 2645 4-CF₃Ph— —H —CH₂COOH —H (CDCl₃) 1.44-1.50(2H, m), 1.90(2H, brd, J = 13.5 Hz), 1.94(1H, m), 2.36 (2H, d, J = 7.0 Hz), 2.75(2H, dt, J = 2.5 Hz, 12.0 Hz), 3.63(2H, brd, J = 12.0 Hz), 6.92(1H, d, J = 9.0 Hz), 6.97(2H, d, J = 9.0 Hz), 7.04(2H, d, J = 9.0 Hz), 7.72(1H, s), 7.78(2H, d, J = 8.0 Hz), 7.99(2H, d, J = 8.0 Hz), 8.19 (1H, dd, J = 9.0 Hz, 2.5 Hz), 8.25(1H, d, J = 2.5 Hz). 2646 3-CF₃Ph— H —CH₂COOH —H (CDCl₃) 1.46-1.49(2H, m), 1.89(2H, brd, J = 15.0 Hz), 1.95(1H, m), 2.36(2H, d, J = 7.0 Hz), 2.74(2H, dt, J = 2.0 Hz, 12.0 Hz), 3.63(2H, brd, J = 12.0 Hz), 6.92(1H, d, J = 9.0 Hz), 6.97(2H, d, J = 9.0 Hz), 7.05 (2H, d, J = 9.0 Hz), 7.66(1H, t, J = 7.5 Hz), 7.73(2H, brs), 7.84(1H, d, J = 7.5 Hz), 8.07(1H, d, J = 7.5 Hz), 8.14(1H, brs), 8.17(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.27(1H, d, J = 2.5 Hz). 2647 4-CF₃Ph— —OCH₃ —CH₂COOH —H (DMSO-d₆ 1.31-1.36 2H, m, 1.77- 1.81(3H, m), 2.21(2H, d, J = 7.4 Hz), 2.68-2.75(2H, m), 3.64(2H, brs), 3.68(3H, s), 6.52(1H, brs), 6.68(1H, brs), 6.89-6.96(2H, m), 7.92(2H, d, J = 8.4 Hz), 8.09 8.17(3H, m), 8.38(1H, d, J = 2.5 Hz), 10.54(1H, s), 12.10(1H, brs). 2648 4-CF₃Ph— —H —COOH —H (CDCl₃ + CD₃OD) 1.82-1.96(2H, m), 2.04-2.09(2H, m), 2.38-2.48(1H, m), 2.74-2.84(2H, m), 3.52-3.61(2H, m), 6.86(1H, dd, J = 8.9 Hz, 0.5 Hz), 6.96-7.05(4H, m), 7.69- 7.76(2H, m), 8.06(2H, d, J = 8.1 Hz), 8.16(1H, d, J = 8.1 Hz), 8.23- 8.33(2H, m).

TABLE 422

Ex- ample No. R₁₁₄₁ R₁₁₄₂ ¹H NMR (DMSO-d₆) δppm 2649 4-CF₃Ph— —CH₃ 1.41(2H, brs), 1.84-1.96(3H, m), 1.97(3H, s), 2.22(2H, d, J = 6.6 Hz), 2.55-2.75(2H, m), 3.58(2H, d, J = 11.9 Hz), 6.72- 7.11(4H, m), 7.52(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.74(1H, d, J = 2.6 Hz), 7.89-7.99(4H, m), 10.49(1H, s), 12.14(1H, brs). 2650 3,4-Cl₂Ph— —CH₃ 1.38(2H, brs), 1.82-1.96(3H, m), 1.97(3H, s), 2.22(2H, d, J = 6.4 Hz), 2.55-2.75(2H, m), 3.59(2H, d, J = 11.9 Hz), 6.88- 6.91(4H, m), 7.51(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.63(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.74(1H, d, J = 2.8 Hz), 7.83-7.87(2H, m), 10.38(1H, s), 12.12(1H, brs). 2651 3,4-Cl₂Ph— —H 1.30-1.37(2H, m), 1.75-1.91(3H, m), 2.20(2H, d, J = 6.9 Hz), 2.51-2.62(2H, m), 3.60(2H, d, J = 12.0 Hz), 6.87-6.94(5H, m), 7.50(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.62(1H, dd, J = 8.6 Hz, 2.3 Hz), 7.77(1H, d, J = 2.8 Hz), 7.84-7.89(2H, m), 10.39(1H, s), 12.09(1H, brs). 2652 4-CF₃Ph— —H 1.29-1.33(2H, m), 1.74-1.91(3H, m), 2.19(2H, d, J = 6.8 Hz), 2.63-2.75(2H, m), 3.59(2H, d, J = 12.2 Hz), 6.86-6.93(5H, m), 7.50(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.77(1H, d, J = 2.6 Hz), 7.89-7.99(4H, m), 10.47(1H, s), 12.09(1H, brs). 2653 4-CF₃Ph— —OCH₃ 1.41(2H, brs), 1.81-1.85(3H, m), 2.25(2H, d, J = 6.4 Hz), 2.55-2.79(2H, m), 3.64(3H, s), 3.68(2H, brs), 6.73-6.95(4H, m), 7.51(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.73(1H, d, J = 2.6 Hz), 7.92-8.02(4H, m), 10.45(1H, s), 12.14(1H, brs). 2654 3,4-Cl₂Ph— —OCH₃ 1.42(2H, brs), 1.79-1.91(3H, m), 2.23(2H, d, J = 6.6 Hz), 2.76-2.83(2H, m), 3.63(5H, brs), 6.63-6.98(4H, m), 7.48(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.63(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.71(1H, d, J = 2.8 Hz), 7.85-7.88(2H, m), 10.36(1H, s), 12.33(1H, brs).

TABLE 423

Ex- ample No. R₁₁₄₃ R₁₁₄₄ ¹H NMR (DMSO-d₆) δppm 2655 4-CF₃Ph— —CH₃ 1.81-1.99(4H, m), 2.00(3H, s), 2.41-2.44(1H, m), 2.75(2H, brs), 3.58(2H, d, J = 12.2 Hz), 6.91-7.20(4H, m), 7.53(1H, dd, J = 8.9 Hz, 2.6 Hz), 7.75(1H, d, J = 2.6 Hz), 7.90- 7.99(4H, m), 10.52(1H, s), 12.41(1H, brs). 2656 3,4-Cl₂Ph— —CH₃ 1.63-1.71(2H, m), 1.91-1.94(2H, m), 1.95(3H, s), 2.41- 2.48(1H, m), 2.75-2.80(2H, m), 3.58(2H, d, J = 12.9 Hz), 6.85-6.89(3H, m), 7.50(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.68- 7.79(2H, m), 7.81-7.98(4H, m), 10.43(1H, s), 12.35(1H, brs). 2657 3,4-Cl₂Ph— —H 1.74(2H, brs), 1.93-1.98(2H, m), 2.49-2.51(2H, m), 2.88(1H, brs), 3.55-3.60(2H, m), 6.90-7.01(5H, m), 7.50- 7.89(5H, m), 10.41(1H, s), 12.13(1H, brs). 2658 4-CF₃Ph— —H 1.66-1.71(2H, m), 1.88-1.92(2H, m), 2.34-2.42(1H, m), 2.68-2.76(2H, m), 3.56(2H, d, J = 12.4 Hz), 6.85-6.92(5H, m), 7.48(1H, d, J = 2.8 Hz), 7.51(1H, d, J = 2.8 Hz), 7.77- 7.99(4H, m), 10.47(1H, s), 12.21(1H, s).

TABLE 424

Ex- ample No. R₁₁₄₅ R₁₁₄₆ ¹H NMR (DMSO-d₆) δppm 2659 —H —CH₂COOH 1.26-1.32(2H, m), 1.74-1.91(3H, m), 2.20(2H, d, J = 6.6 Hz), 2.66(2H, t, J = 11.0 Hz), 3.63(2H, d, J = 12.5 Hz), 6.93-7.03(4H, m), 7.13-7.35(2H, m), 7.65(2H, d, J = 8.6 Hz), 8.42(1H, d, J = 2.3 Hz), 8.47(1H, d, J = 2.3 Hz), 11.00(1H, s), 12.07(1H, brs). 2660 —CH₃ —CH₂COOH 1.30-1.41(2H, m), 1.80-2.00(3H, m), 1.99(3H, s), 2.20(2H, d, J = 6.6 Hz), 2.68-2.76(2H, m), 3.62(2H, d, J = 12.2 Hz), 6.88-6.96(3H, m), 7.33(2H, d, J = 8.2 Hz), 7.65(2H, d, J = 8.6 Hz), 8.44(2H, s), 11.00(1H, s), 12.10(1H, brs). 2661 —H —COOH 1.63-1.70(2H, m), 1.88-1.92(2H, m), 2.41-2.45(1H, m), 2.71-2.79(2H, m), 3.61(2H, d, J = 12.5 Hz), 6.93-7.00(4H, m), 7.31(2H, d, J = 8.6 Hz), 7.63(2H, d, J = 8.7 Hz), 8.40- 8.47(2H, m), 10.63(1H, s), 12.21(1H, s).

TABLE 425

Example No. R₁₁₄₇ ¹H NMR (DMSO-d₆) δppm 2662 4-CF₃PhCO— 2.08(3H, s), 2.09-2.32(2H, m), 3.65-3.93(4H, m), 7.01(1H, d, J = 8.6 Hz), 7.06(1H, d, J = 8.9 Hz), 7.19(1H, dd, J = 2.6 Hz, 8.6 Hz), 7.29(1H, d, J = 2.6 Hz), 7.42-7.51(2H, m), 7.81-7.98(4H, m), 8.10-8.18(2H, m), 8.21(1H, dd, J = 2.6 Hz, 8.9 Hz), 8.43(1H, d, J = 2.6 Hz), 10.60(1H, s), 12.60-12.91(1H, m). 2663 3,4-Cl₂PhSO₂— 1.99(3H, s), 2.07-2.31(2H, m), 3.60-3.91(4H, m), 6.97(H, d, J = 8.5 Hz), 6.98(1H, d, J = 8.8 Hz), 7.16(1H, dd, J = 2.4 Hz, 8.5 Hz), 7.25(1H, d, J = 2.2 Hz), 7.40-7.51(2H, m), 7.54(1H, dd, J = 2.8 Hz, 8.8 Hz), 7.62(1H, dd, J = 2.2 Hz, 8.5 Hz), 7.75(1H, d, J = 2.8 Hz), 7.79-7.93(4H, m).

Example 2664 Production of (4-{5-[(4-trifluoromethylphenylamino)methyl]-pyridin-2-yloxy}phenyl)(4-piperonylpiperazin-1-yl)methanone

Methanesulfonic acid 6-[4-(4-piperonylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl ester (0.433 g, 0.824 mmol) and 4-trifluoromethyl phenylamine (0.310 mL, 2.47 mmol) were mixed together, and the resulting mixture was stirred for 2 hours at 100° C. The formed yellow mass was stirred together with a saturated sodium bicarbonate solution, ethyl acetate and THF (20 ml of each). The organic layer was collected, washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica g column chromatography (dichloromethane:methanol=50:1), to thereby yield 0.236 g of the title compound.

Appearance: Pale yellow amorphous powder

¹H NMR (CDCl₃) δ 2.44 (4H, brs), 3.45 (2H, s), 3.57 (2H, brs), 3.75 (2H, brs), 4.30-4.35 (1H, m), 4.36 (2H, s), 5.95 (2H, s), 6.63 (2H, d, J=8.7 Hz), 6.74-6.77 (2H, m), 6.85 (1H, s), 6.93 (1H, d, J=8.4 Hz), 7.15 (2H, d, 8.4 Hz), 7.39-7.47 (4H, m), 7.71 (1H, dd, J=2.5 Hz, 8.4 Hz), 8.18 (1H, d, J=2.3 Hz).

The following compounds were produced in the same manner as in Example 2664.

TABLE 426

Example No. R₁₁₄₈ Xb₇₆ Xb₇₇ Form ¹H NMR (solvent) δppm 2665 3,4-Cl₂Ph— —N(CH₃)— CH₂ free (CDCl₃) 2.42-2.44(4H, m), 3.03(3H, s), 3.43(2H, brs), 3.49-3.50(2H, m), 3.63(2H, brs), 4.08(2H, s), 4.94(2H, s), 5.94(2H, s), 6.70(2H, d, J = 9.2 Hz), 6.74(2H, brs), 6.80(1H, dd, J = 8.9 Hz, 2.8 Hz), 6.83-6.86(2H) 7.01(2H, d J = 9.1 Hz), 7.05(1H, d, J = 2.8 Hz), 7.32(1H, d, J = 8.9 Hz), 7.86(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.19(1H, d, J = 1.8 Hz). 2666 4-CF₃Ph— —N(CH₃)— —CH₂— free (CDCl₃) 2.41-2.44(4H, m), 3.03(3H, s), 3.43(2H, brs), 3.49(2H, brs), 3.63(2H, brs), 4.08(2H, s), 5.02(2H, s), 5.95(2H, s), 6.69-6.74(4H, m), 6.85-6.88(2H, m), 7.00-7.03(4H, m), 7.56(2H, d, J = 8.6 Hz), 7.72(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.22(1H, d, J = 2.3 Hz). 2667 4-CF₃Ph— none none hydro- (DMSO-d₆) 3.10-3.42(8H, m), 4.24(2H, chloride brs), 5.20(2H, s), 6.07(2H, s), 6.97- m), 7.15(1H, d, J = 8.6 Hz), 7.21-7.24(1H, m), 7.52(2H, d, J = 8.6 HO, 7.68(2H, d, J = 8.7 Hz), 8.01(1H, dd, J = 2.5 Hz, 8.4 Hz), 8.29(1H, d, J = 2.3 Hz), 11.00(1H, brs).

Example 2668 Production of 2-(methyl-{4-[5-(5-trifluoromethylpyridin-2-yloxymethyl)pyridin-2-yloxy]phenyl}amino)-1-(4-piperonylpiperazin-1-yl)ethanone

2-{[4-(5-hydroxymethylpyridin-2-yloxy)phenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone (0.98 g, 2.0 mmol) was dissolved in DMF (30 mL). To the resulting solution was added 60% sodium hydride (60%, 88 mg, 2.2 mmol) under ice cooling, and this solution was stirred for 30 minutes at 0° C. To the reaction solution was added 2-chloro-5-(trifluoromethyl)pyridine (0.36 g, 2.0 mol), and this solution was stirred under a nitrogen atmosphere for 3 hours at 60° C. The resulting reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and this solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:5), to thereby yield 0.68 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.41-2.44 (4H, m), 3.02 (3H, s), 3.43 (2H, s), 3.48 (2H, brs), 3.63 (2H, brs), 4.08 (2H, s), 5.37 (2H, s), 5.94 (2H, s), 6.68-6.77 (4H, m), 6.81-6.84 (3H, m), 7.00 (2H, d, J=9.1 Hz), 7.72-7.79 (2H, m), 8.27 (1H, d, J=2.3 Hz), 8.44 (1H, brs).

The following compounds were produced in the same manner as in Example 2668.

TABLE 427

Example No. R₁₁₄₉ mp (° C.) 2669 4-CF₃Ph— 165.0-166.0 2670 3-CF₃Ph— 163.0-165.0 2671 3,4-Cl₂Ph— 160.0-161.5

Example 2672 3,4-dichloro-N-{6-[4-(3,5-dioxoisoxazolidine-4-ylidenemethyl)phenoxy]pyridin-3-yl}benzamide

TO a solution of hydroxylamine hydrochloride (500 mg, 1.0 mmol) in water (0.2 mL) were added sodium carbonate (1.05 g, 9.91 mmol) and a solution of 2-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzylidene}malonic acid dimethyl ester (500 mg, 1.0 mmol) in THF (5 mL). To the resulting solution was subsequently added methanol (5 mL) and stirred for 8 hours at 60° C. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). To the resulting white precipitate was added ethyl acetate, filtered, and the filtrate was washed with diethyl ether, to thereby yield 105 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 7.12 (1H, d, J=8.9 Hz), 7.14 (2H, d, J=8.8 Hz), 7.63 (2H, d, J=8.8 Hz), 7.84 (1H, d, J=8.4 Hz), 7.95 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.15 (1H, s), 8.22 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.51 (1H, d, J=2.6 Hz), 10.57 (1H, s), 11.16 (1H,

Example 2673 Production of 3,4-dichloro-N-{6-[4-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)phenoxy]pyridin-3-yl}benzamide monohydrochloride

To 3,4-dichloro-N-{6-[4-(N-acetoxycarbamimidoylmethyl)phenoxy]pyridin-3-yl}benzamide (340 mg, 0.788 mmol) was added acetic acid (4 mL), and the resulting solution was stirred under reflux for 10 minutes. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1), and the obtained reside was dissolved in ethyl acetate (5 mL). To this solution was added a solution of 4 N hydrogen chloride in ethyl acetate until the compound no longer precipitated out. The obtained white powder was filtered, and washed with diethyl ether, to thereby yield 154 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.55 (3H, s), 4.05 (2H, s), 7.07 (1H, d, J=8.7 Hz), 7.07 (2H, d, J=8.6 Hz), 7.33 (2H, d, 8.6 Hz), 7.83 (1H, d, J=8.4 Hz), 7.96 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.21 (1H, dd, J=8.7 Hz, 2.6 Hz), 8.24 (1H, d, J=2.0 Hz), 8.48 (1H, d, J=2.6 Hz), 10.62 (1H, s).

Example 2674 Production of 1-(3-{4-[5-(3,4-dichlorobenzoylamino)-2-pyridylmethyl]phenyl}propionyl)-4-piperonylpiperazine monohydrochloride

To a solution of ethyl 3-(4-{5-[bis(3,4-dichlorobenzoyl)amino]2-pyridylmethyl}phenyl) propionate (177 mg, 0.281 mmol) in THF (5 mL) and ethanol (5 mL) were added 5 M aqueous sodium hydroxide (0.0929 mL, 0.463 mmol) and water (1 mL), and the resulting solution was refluxed for 1 hour. To this reaction solution was added 5 M hydrochloric acid (0.12 mL), and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was dissolved in DMF (3 mL), and to the resulting solution were then added 1-piperonylpiperazine (102 mg, 0.463 mmol), triethylamine (0.137 mL, 0.983 mmol) and diethyl cyanophosphonate (0.0703 mL, 463 mmol), and stirred for 1.5 hours at room temperature. Water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=70:1→40:1→20:1), to thereby yield 44.1 mg of a free form. This free form was dissolved in ethanol (5 mL) and 5 M hydrochloric acid (0.03 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from water-containing isopropanol, to thereby yield 19.6 mg of the title compound.

Appearance: Pale yellow powder

Melting point: 181-183° C.

Example 2675 Production of N-(6-{4-[4-(5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-ylmethyl)piperazine-1-carbonyl]-phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide monooxalate

To a suspension of N-{6-[4-(4-hydrazinocarbonylmethylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide trihydrochloride (300 mg, 0.46 mmol) in THF (7 mL) was added triethylamine (0.29 mL, 2.08 mmol), and the resulting solution was stirred for 10 minutes at room temperature. To the solution was added N,N′-carbonyldiimidazole (97 mg, 0.60 mmol) under ice cooling, and the resulting solution was stirred for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform:methanol=15:1). The obtained residue was dissolved in ethanol, and to the resulting solution was added oxalic acid. Ethanol was evaporated under reduced pressure, after which the solidified white substance was filtered, and washed with diethyl ether, to thereby yield 140 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.31-2.69 (4H, m), 3.53 (2H, s), 3.53 (4H, brs), 7.16 (1H, d, J=8.9 Hz), 7.17 (2H, d, J=8.5 Hz), 7.45 (2H, d, J=8.5 Hz), 7.94 (2H, d, J=8.1 Hz), 8.17 (2H, d, J=8.1 Hz), 8.26 (1H, dd, J=8.9 Hz, 2.7 Hz), 8.55 (1H, d, J=2.7 Hz), 10.67 (1H, s), 12.27 (1H, s).

Example 2676 Production of 4-(4-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}-4-hydroxybutyryl)morpholine

To a suspension of 4-(4-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}-4-oxobutyryl)morpholine (1.00 g, 1.83 mmol) in THF (20 mL) and methanol (5 mL) was added sodium borohydride (0.0694 g, 1.83 mmol), and the resulting solution was stirred for 1 hour at room temperature. To this reaction solution were added water and saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). The obtained solid was recrystallized from water-containing isopropanol, to thereby yield 0.850 g of the title compound.

Appearance: White powder

Melting point: 108-111° C.

The following compounds were produced in the same manner as in Example 2676.

TABLE 428

Ex- ample No. R₁₁₅₀ Form mp (° C.) 2677 morpholino free 142-145 2678

free 150-152 2679

hydro- chloride 197-199 2680

hydro- chloride 222-225

TABLE 429

Ex- ample No. Xb₇₈ R₁₁₅₁ Form mp (° C.) or ¹H NMR 2681 —O—

free ¹H NMR (DMSO-d₆) δ 2.38- 2.54(6H, m), 3.58(4H, t, J = 4.5 Hz), 4.73-4.77(1H, m), 5.06 (1H, d, J = 3.8 Hz), 7.04-7.07(3H, m), 7.38(2H, d, J = 8.4 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 1.2 Hz), 8.22(1H, d, J = 2.0 Hz), 8.19(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.48(1H, d, J = 2.6 Hz), 10.55(1H, brs). 2682 —CH(OH)—

oxalate mp 102-108

TABLE 430

Example No. R₁₁₅₂ Xb₇₉ ¹H NMR (CDCl₃) δppm 2683 —OCH₃ —CH₂— 2.30-2.39(4H, m), 2.57-2.62(2H, m), 2.90-2.95(2H, m), 3.36- 3.43(4H, m), 3.58-3.61(2H, m), 3.70(3H, s), 5.83(1H, s), 5.93(2H, s), 6.69-6.88(6H, m), 6.99(1H, d, J = 8.1 Hz), 7.47- 7.62(5H, m), 8.07(1H, d, J = 2.3 Hz). 2684 —H —N(CH₃)— 2.38-2.43(4H, m), 2.99(3H, s), 3.42-3.60(6H, m), 4.05(2H, s), 5.77(1H, s), 5.94(2H, s), 6.64-6.84(6H, m), 6.93-6.99(2H, m), 7.47(2H, d, J = 8.1 Hz), 7.53-7.59(3H, m), 8.10(1H, d, J = 2.1 Hz).

Example 2685 Production of {6-[4-(4-piperonylpiperazin-1-ylmethyl)phenoxy]pyridin-3-ylmethyl}-(4-trifluoromethylphenyl)amine

To a suspension of lithium aluminum hydride (0.106 g, 2.80 mmol) in THF (10 mL) was added dropwise a solution of 6-[4-(4-piperonylpiperazine-1-carbonyl)phenoxy]-N-(4-trifluoromethylphenyl)nicotinamide (0.423 g, 0.700 mmol) in THF (10 mL) under ice cooled stirring. Once the entire amount was added dropwise, the solution temperature was slowly raised, and stirred under reflux for 2 hours. After cooling, ice water (50 mL) was added to the solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1), to thereby yield 0.125 g of the title compound.

Appearance: Pale Yellow oil

MS 576 (M⁺)

The following compounds were produced in the same manner as in Example 2685.

Example 2686 N-[6-(2-fluoro-4-{methyl[2-(4-piperonylpiperazin-1-yl)ethyl]amino}phenoxy)pyridin-3-yl]-3,4-dichlorobenzenesulfonamide

¹H NMR (CDCl₃) δ 2.50-2.55 (10H, m), 2.92 (3H, s), 3.41-3.45 (4H, m), 5.93 (2H, s), 6.39-6.49 (2H, m), 6.73-6.74 (2H, m), 6.84-6.89 (2H, m), 6.99 (1H, t, J=9.1 Hz), 7.42-7.70 (4H, m), 7.81 (1H, brs).

Example 2687 Production of 3-(3-methyl-4-{5-[2-(4-trifluoromethylphenyl)ethyl]pyridin-2-yloxy}phenyl)-1-piperonyltetrahydropyrimidin-2-one hydrobromide

To a solution of 3-(3-methyl-4-{5-[(E)-2-(4-trifluoromethylphenyl)vinyl]pyridin-2-yloxy}phenyl)-1-piperonyltetrahydropyrimidin-2-one (0.16 g, 6.27 mmol) in ethyl acetate (15 mL) was added 5% platinum-carbon (0.05 g) under a nitrogen atmosphere, and the resulting solution was then stirred under a hydrogen atmosphere for 4.5 hours at room temperature. The resulting reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:=n-hexane 1:4-1:2), and to the resulting product was added hydrobromide, to thereby yield 50 mg of the title compound.

Appearance: Colorless amorphous powder

¹H NMR (DMSO-d₆) δ 1.85-2.09 (5H, m), 2.77-3.02 (4H, m), 3.15-3.33 (2H, m), 3.55-3.70 (2H, m), 3.75-4.15 (1H, m), 4.40 (2H, s), 5.99 (2H, s), 6.76 (1H, dd, J=1.5 Hz, 7.8 Hz), 6.80-6.98 (4H, m), 7.10 (1H, dd, J=2.6 Hz, 8.5 Hz), 7.19 (1H, d, J=2.6 Hz), 7.44 (2H, d, J=8.1 Hz), 7.62 (2H, d, J=8.1 Hz), 7.71 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.91 (1H, d, J=2.4 Hz).

The following compounds were produced in the same manner as in Reference Example 673.

TABLE 431

Example No. R₁₁₅₃ R₁₁₅₄ M ¹H NMR (CDCl₃) δppm 2688 —H piperonyl 1 1.31-1.45(2H, m), 1.84-2.02(3H, m), 2.30(2H, d, J = 6.8 Hz), 2.41-2.43(4H, m), 2.72(2H, t, J = 12.2 Hz), 3.43(2H, s), 3.44-3.65(6H, m), 5.95(2H, s), 6.71- 6.77(2H, m), 6.85-7.00(6H, m), 7.21-7.26(3H, m), 7.51(2H, d, J = 8.6 Hz), 7.98(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.60(1H, d, J = 2.6 Hz). 2689 —H —H 1 1.38-1.46(2H, m), 1.84-2.00(3H, m), 2.31(2H, d, J = 6.8 Hz), 2.71(2H, t, J = 12.2 Hz), 2.86-2.89(4H, m), 3.48-3.63(7H, m), 6.86-6.99(5H, m), 7.23-7.29(3H, m), 7.49(2H, d, J = 8.4 Hz), 7.97(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.60(1H, d, J = 2.1 Hz). 2690 —CH₃ piperonyl 1 1.36-1.40(2H, m), 1.82-2.02(3H, m), 2.03(3H, s), 2.30(2H, d, J = 6.8 Hz), 2.41-2.43(4H, m), 2.68(2H, t, J = 12.0 Hz), 3.43(2H, s), 3.49-3.65(6H, m), 5.94(2H, s), 6.74-6.89(8H, m), 7.24(2H, d, J = 8.2 Hz), 7.49(2H, d, J = 8.6 Hz), 7.99(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.58(1H, d, J = 2.1 Hz). 2691 —H piperonyl 0 1.78-2.03(4H, m), 2.46(4H, brs), 2.55-2.77(3H, m), 3.46(2H, s), 3.55(2H, brs), 3.67(4H, brs), 5.95(2H, s), 6.75-6.78(2H, m), 6.85-7.01(6H, m), 7.21- 7.26(3H, m), 7.52(2H, d, J = 8.6 Hz), 7.98(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.60(1H, d, J = 2.5 Hz).

Example 2692 Production of 1-[3-(4-{1-[5-(3,4-dichlorobenzoylamino)-2-pyridyl]-1-hydroxyimino}methylphenyl)propionyl]-4-piperonylpiperazine

To a solution of 1-(3-{4-[5-(3,4-dichlorobenzoylamino)pyridine-2-carbonyl]phenyl}propionyl)-4-piperonylpiperazine (0.330 g, 0.511 mmol) in pyridine (7 mL) was added hydroxylamine hydrochloride (53.3 mg, 0.767 mmol), and the resulting solution was refluxed for 0.5 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added brine. This solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=15:1), whereby 0.225 g of the title compound was obtained as a mixture of the syn form and the anti form (1:1) of the oxime.

Appearance: Colorless amorphous powder

¹H NMR (CDCl₃) δ 2.21-2.39 (4H, m), 2.49-2.60 (2H, m), 2.78-2.90 (2H, m), 3.29-3.44 (4H, m), 3.55 (2H, s), 5.90 (2H, s), 6.62-6.73 (2H, m), 6.80 (1H, s), 7.07 (1H, d, J=7.7 Hz), 7.12 (1H, d, J=7.7 Hz), 7.15-7.30 (2.5H, m), 7.39 (0.5H, d, J=8.4 Hz), 7.42 (0.5H, d, J=8.4 Hz), 7.45-7.51 (0.5H, m), 7.62-7.74 (1H, m), 7.94 (0.5H, d, J=2.0 Hz), 7.99 (0.5H, d, J=2.0 Hz), 8.09-8.28 (1H, m), 8.62 (0.5H, s), 8.85 (0.5H, s), 9.40 (0.5H, brs), 9.62 (0.5H, brs), 10.21 (0.5H, brs), 13.85 (0.5H, brs).

Example 2693 Production of 4-(2-oxo-3-{4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]phenyl}propionyl)piperazine-1-carboxylic acid t-butyl ester

To a solution of 4-(2-hydroxy-3-{4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]phenyl}propionyl)piperazine-1-carboxylic acid butyl ester (0.58 g, 0.94 mmol) in dichloromethane (4 mL) was added a Dess-Martin reagent (0.8 g, 1.89 mmol), and the resulting solution was then stirred under a nitrogen gas flow for 4 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added 1 N aqueous sodium hydroxide (50 mL), and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (dichloromethane:methanol=50:1), to thereby yield 0.31 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 1.41 (9H, s), 2.99-3.22 (4H, m), 3.25-3.41 (2H, m), 3.42-3.60 (2H, m), 4.04 (2H, s), 6.97 (1H, d, J=8.9 Hz), 7.10 (2H, d, J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=8.0 Hz), 8.13 (1H, d, J=2.8 Hz), 8.30 (18, dd, J=8.9 Hz, 2.8 Hz), 8.45 (1H, brs).

Example 2694 Production of 3,4-dichloro-N-{3-fluoro-4-[4-(1-hydroxy-2-morpholine-4-ylethyl)phenoxy]phenyl}benzamide

3,4-Dichloro-N-{3-fluoro-4-[4-(1-hydroxy-2-morpholine-4-ylethyl)phenoxy]phenyl}benzamide (37.4 g) was recrystallized from ethanol (700 mL) to yield 34.34 g of the title compound.

Appearance: White powder

Melting point: 175-176° C.

Example 2695 Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzenesulfonamide

N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzenesulfonamide (8.15 g) was recrystallized from ethanol (60 mL) to yield 7.78 g of the title compound.

Appearance: White powder

Melting point: 163-166° C.

Example 2696 Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide

N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (5.1 g, 7.7 mmol) was recrystallized from acetone (15 mL) to yield 3.7 g of the title compound.

Appearance: White powder

Melting point: 128-131° C.

Example 2697 Production of N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide

N-{6-[4-(4-Benzylpiperazine-1-carbonyl)phenoxy]pyridin-]-yl}-4-trifluoromethylbenzamide (78.86 g) was recrystallized from ethanol (530 mL) to yield 96.66 g of the title compound.

Appearance: White needles

Melting point: 177.6-179.2° C.

Example 2698 Production of N-(6-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinoline-6-ylmethyl)piperazine-1-carbonyl]phenoxy}-pyridin-3-yl)-4-trifluoromethylbenzamide

To a solution of 4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]benzoic acid (4.30 g, 10.7 mmol) in DMF (150 mL) were added 1-(2-oxo-1,2,3,4-tetrahydroquinoline-6-ylmethyl)piperazine (2.6 g, 10.7 mmol), 1-hydroxybenzotriazole monohydrate (1.64 g, 10.7 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.46 g, 12.8 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling and for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 5.24 g of the title compound.

Appearance: White powder

Melting point: 250.5-252.5° C.

Example 2699 Production of N-(6-{4-[4-(4-benzylpiperidine-1-carbonyl)piperazine-1-carbonyl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide

To a solution of 1-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzoyl}piperidine-4-carboxylic acid (4.5 g, 8.8 mmol) in DMF (88 mL) were added 1-benzylpiperazine (1.83 mL, 10.5 mmol), 1-hydroxybenzotriazole monohydrate (1.61 g, 10.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.02 g, 10.5 mmol) under ice cooling, and the resulting solution was stirred overnight at room temperature. To this reaction solution was added a saturated sodium bicarbonate solution, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from isopropyl alcohol (700 mL), to thereby yield 3.2 g of the title compound.

Appearance: White powder

Melting point: 223-225° C.

Example 2700 Production of N-[6-(4-{[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide

To a suspension of 1-(4-benzylpiperazin-1-yl)-2-{methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}ethanone (2.85 g, 6.0 mmol) in ethyl acetate (30 mL) was added 5% platinum-carbon (0.30 g) under a nitrogen atmosphere, and the resulting solution was stirred for 3 hours at 40° C. under a hydrogen atmosphere. The platinum-carbon was separated off with Celite, and the filtrate was concentrated. The residue was dissolved in THF (30 mL), and to this solution was added triethylamine (1.26 mL, 9.1 mmol) under ice cooling. To the resulting solution was then added dropwise 4-(trifluoromethyl)benzoyl chloride (1.16 mL, 7.8 mmol). This reaction solution was stirred overnight, then a saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The resulting product was then recrystallized from a mixed solvent consisting of diisopropyl ether-acetone, to thereby yield 1.37 g of the title compound.

Appearance: White powder

Melting point: 112-113° C.

Example 2701 Production of (4-benzylpiperazin-1-yl)(4-{5-[methyl(4-trifluoromethylbenzyl)amino]pyridin-2-yloxy}phenyl)methanone

To a solution of (4-benzylpiperazin-1-yl){4-[5-(4-trifluoromethylbenzylamino)pyridin-2-yloxy]phenyl}methanone (5.40 g, 9.88 mmol) in methanol (150 mL) were added 37% aqueous formaldehyde (2.8 mL), sodium cyanoborohydride (1.86 g, 29.6 mmol) and acetic acid (1.7 mL) under ice cooling, and the resulting solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. Water was added to the residue, and this solution was neutralized with a saturated sodium bicarbonate solution, and extracted with chloroform. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=60:1). To the resulting product was then added a solution of 4 M hydrogen chloride in ethyl acetate until the resulting solution had a pH of 1. The precipitates were collected by filtration and recrystallized from ethanol (80 mL), to thereby yield 2.5 g of the title compound.

Appearance: White powder

Melting point: 180-183.5° C.

Example 2702 Production of 4-piperonylpiperazine-1-carboxyl 4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzylamide hydrochloride

To a solution of 4-piperonylpiperazine-1-carboxyl 4-(5-aminopyridin-2-yloxy)benzylamide (2.48 g, 5.4 mmol) in THF (50 mL) were added triethylamine (0.9 mL, 6.5 mmol) and 3,4-dichlorobenzoyl chloride (1.13 g, 5.4 mmol) under ice cooling, and the resulting solution was stirred under ice cooling for 10 minutes. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=25:1) to yield 2.97 g of a white powder. This white powder was dissolved in ethanol (45 mL), and to the resulting solution was added a solution of 4 M hydrogen chloride in ethyl acetate until the solution had a pH of 1. The precipitates were collected by filtration and recrystallized from 83% ethanol (36 mL), to thereby yield 2.72 g of the title compound.

Appearance: White powder

Melting point: 243.5-246.5° C.

Example 2703 Production of N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide

N-[6-(4-{4-[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide (1.35 g) was recrystallized from ethanol (20 mL) to yield 1.23 g of the title compound.

Appearance: White powder

Melting point: 156-158° C.

Example 2704 Production of N-(6-{4-[4-(4-piperonylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide

N-(6-{4-[(4-(4-Piperonylpiperidine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide (1.95 g) was recrystallized from ethanol (35 mL) to yield 1.70 g of the title compound.

Appearance: White powder

Melting point: 130-133° C.

Example 2705 Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide

N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (0.86 g, 1.30 mmol) was recrystallized from a mixed solvent of acetone (3 mL) diethyl ether (4 mL) and n-hexane (1 mL) to yield 0.72 g of the title compound.

Appearance: Pale yellow powder

Melting point: 154-155° C.

Example 2706 Production of N-(6-{4-[4-(4-benzylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzensulfonamide

N-(6-{4-[4-(4-Benzylpiperidin-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzensulfonamide (1.55 g) was recrystallized from ethanol (60 mL) to yield 1.41 g of the title compound.

Appearance: White powder

Melting point: 199-201° C.

Example 2707 Production of N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzenesulfonamide

To a solution of (1-{4-[5-(3,4-dichlorobenzenesulfonylamino)pyridin-2-yloxy]-3-methylphenyl}piperidine-4-yl)acetic acid (1.70 g, 3.1 mmol) and 1-benzylpiperazine (0.71 g, 4.0 mmol) in DMF (40 mL) were added triethylamine (1.08 mL, 7.8 mmol) and diethyl cyanophosphonate (0.76 g, 4.3 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling. To this reaction solution was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1), after which the resulting product was recrystallized from ethanol, to thereby yield 1.61 g of the title compound.

Appearance: White needles

Melting point: 151-155° C.

Example 2708 Production of N-[6-(4-{[2-(4-benzothiazole-6-ylmethylpiperazin-1-yl)-2-oxoethyl]methylamino}-phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride

To a solution of ({4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}methylamino)acetic acid (1.02 g, 2.3 mmol) and 1-(benzothiazole-6-ylmethyl)piperazine (0.58 g, 2.5 mmol) in DMF (15 mL) were added triethylamine (0.95 mL, 6.9 mmol) and diethyl cyanophosphonate (0.447 mL, 2.7 mmol) under ice cooling, and the resulting solution was stirred for 30 minutes under ice cooling and for 45 minutes at room temperature. Water was added to the solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to obtain 1.28 g of a white powder. This white powder was dissolved in ethanol (15 mL), and to the resulting solution was added a solution of 4 M hydrogen chloride in ethyl acetate until the resulting solution had a pH of 1. The precipitates were collected by filtration and recrystallized from 85% ethanol (30 mL), to thereby yield 1.06 g of the title compound.

Appearance: White powder

Melting point: 202-223° C.

Example 2709 Production of 3,4-dichloro-N-{6-[4-({2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)piperazin-1-yl]-2-oxoethyl}methylamino)phenoxy]pyridin-3-yl}benzamide maleate

To a solution of ({4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}methylamino)acetic acid (2.50 g, 5.6 mmol) in DMF (55 mL) were added 1-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)piperazine (1.7 g, 7.3 mmol), 1-hydroxybenzotriazole monohydrate (0.86 g, 5.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.29 g, 6.7 mmol) under ice cooling, and the resulting solution was stirred for 30 minutes under ice cooling and for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was dissolved in ethanol (30 mL). To the resulting solution was added maleic acid (0.32 g, 2.7 mmol), and this solution was left to stand. The precipitates were collected by filtration, to thereby yield 1.45 g of the title compound.

Appearance: Pale yellow powder

Melting point: 188-190° C.

Example 2710 Production of N-(6-{4-[4-(4-benzylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide

N-(6-{4-[4-(4-Benzylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide (0.79 g) was recrystallized from ethanol (15 mL) to yield 0.67 g of the title compound.

Appearance: White powder

Melting point: 185-189° C.

Example 2711 Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-pyrrole-1-ylbenzamide

N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-pyrrole-1-ylbenzamide (2.49 g) was recrystallized from a mixed solvent consisting of acetone (20 mL) and diethyl ether (30 mL) to yield 2.26 g of the title compound.

Appearance: Pale yellow powder

Melting point: 163.1-166.5° C.

Example 2712 Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide

N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide (8.18 g) was recrystallized from a mixed solvent consisting of ethyl acetate (70 mL) and n-hexane (20 mL) to yield 6.93 g of the title compound.

Appearance: White powder

Melting point: 177.8-180.1° C.

Example 2713 Production of 6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl]-2-methylphenoxy}pyridine-3-sulfonyl-(4-trifluoromethylphenyl)amide

6-(4-{4-[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl]-2-methylphenoxy}pyridine-3-sulfonyl-(4-trifluoromethylphenyl)amide (1.50 g) was recrystallized from ethanol (20 mL) to yield 1.40 g of the title compound.

Appearance: White powder

Melting point: 156-160° C.

Example 2714 Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide

N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (2.1 g, 3.2 mmol) was heated to dissolve in acetone (5 mL), and to the resulting solution was then added diethyl ether (10 mL), whereby recrystallization yielded 2.0 g of the title compound.

Appearance: White powder

Melting point: 113-116° C.

Example 2715 Production of 3,4-dichloro-N-{3-fluoro-4-[4-(1-hydroxy-2-morpholine-4-ylethyl)phenoxy]phenyl}benzamide

3,4-Dichloro-N-{3-fluoro-4-[4-(1-hydroxy-2-morpholine-4-ylethyl)phenoxy]phenyl}benzamide (5 g) was recrystallized from ethyl acetate-n-hexane to yield 4.73 g of the title compound.

Appearance: White powder

Melting point: 169-170° C.

Example 2716 Production of N-(6-{4-[4-(4-piperonylpiperazine-1-carbonyl)piperidine-1-carbonyl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide

To a solution of 1-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzoyl}piperidine-4-carboxylic acid (7.96 g, 15.5 mmol) in DMF (160 mL) were added 1-piperonylpiperazine (3.75 g, 17.6 mmol), 1-hydroxybenzotriazole monohydrate (2.85 g, 18.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.56 g, 18.6 mmol) under ice cooling, and the resulting solution was stirred for overnight at room temperature. This reaction solution was concentrated under reduced pressure. To the residue were added water and ethyl acetate, and the resulting solution was vigorously stirred. The resulting precipitates were collected by filtration and recrystallized from a dichloromethane-methanol mixed solvent, to thereby yield 7.36 g of the title compound.

Appearance: White powder

Melting point: 236-238° C.

Example 2717 Production of N-{6-[(4-[4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]-pyridin-3-yl]-4-trifluoromethylbenzamide

To a solution of [1-(4-{methyl[5-(4-trifluoromethylbenzoylamino)pyridin-2-yl]amino}phenyl)piperidine-4-yl]acetic acid (0.80 g, 1.6 mmol) in DMF (10 mL) were added 1-piperonylpiperazine (0.41 g, 1.9 mmol), 1-hydroxybenzotriazole monohydrate (0.24 g, 1.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.39 g, 2.0 mmol) under ice cooling, and the resulting solution was stirred for 3 hours at room temperature. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with dichloromethane. The dichloromethane layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The resulting product was then recrystallized from a mixed solvent consisting of 95% ethanol-dichloromethane, to thereby yield 1.05 g of the title compound.

Appearance: White powder

Melting point: 210-212° C.

Formulation Example 1

100 g of the N-[6-(4-{4-[2-(piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide obtained in Example 319, 40 g of Avicel (Tradename, manufactured by Asahi Kasei Corporation), 30 g of cornstarch and 2 g of magnesium stearate were mixed and ground together. The resulting mixture was then formed into a sugar-coated R 10-mm-tablets using a pestle. The obtained tablets were coated with a film coating agent containing 10 g of TC-5 (Tradename, manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropylmethyl cellulose), 3 g of polyethylene glycol 6000, 40 g of castor oil and a suitable amount of ethanol, to thereby prepare a film-coated tablet.

Pharmacological Test

LI90 cells, a human stellate cell line, were seeded on 12-well plastic plates in DMEM (DULBECCO'S modified eagle medium) supplemented with 10% fetal bovine serum, and were cultured for 24 hours in a carbon dioxide (CO₂) incubator (set temperature: 37° C., set CO₂ concentration: 5%). The cultured cells were then washed with D-PBS(−) (DULBECCO's phosphate buffered saline), and subsequently further cultured for 3 days in MEM (Eagle's minimum essential medium) supplemented with 0.1% fetal bovine serum. The cultured cells were again washed with D-PBS(−), and cultured for 16 hours in MEM (0.1% fetal bovine serum with respect to a total MEM volume) which contained a test compound and 10 pM h-TGF-β1 (human transforming growth factor β1). Next, the cultured LI90 cells were washed with D-PBS(−), and cultured for 24 hours in MEM containing ³H-proline (radioactive labelled compound) and 0.25 mM ascorbic acid. The produced collagen was labelled with RI (radioactive isotope). From this culture supernatant, an acid-soluble fraction was extracted. Radioactivity was measured for this fraction. The measured value was taken to be the collagen synthesis activity.

Radioactivity of the culture supernatant cultured with the test compound was compared with that of the culture supernatant cultured without the test compound to calculate a collagen synthesis inhibitory activity (T/C) and determine a concentration (μM) at which collagen synthesis was inhibited by 50% (IC50=a concentration of the test compound at which T/C corresponded to 0.5).

T/C=(Radioactivity of culture supernatant cultured with the test compound)/(radioactivity of culture supernatant cultured without the test compound)

These results are shown in Table 432.

TABLE 432 Collagen synthesis inhibitory activity Text compound IC50 (μM) Example No. 148 0.0230 Example No. 305 0.0069 Example No. 319 0.0019 Example No. 433 0.0130 Example No. 582 0.0370 Example No. 590 0.0380 Example No. 592 0.0950 Example No. 768 0.0860 Example No. 790 0.0055 Example No. 800 0.0290 Example No. 1039 0.0220 Example No. 1049 0.0490 Example No. 1110 0.0390 Example No. 1503 0.0078 Example No. 2063 0.0300 Example No. 2100 0.0790 Example No. 2322 0.0640 Example No. 2362 0.0440 Example No. 2600 0.0220 Example No. 2601 0.0260 

1. A method for producing aromatic compound represented by the following general formula (1) or a salt thereof:

[wherein X₁ represents a nitrogen atom or a group —CH═, R¹ represents a group —Z—R⁶, Z represents a group —N(R⁸)—B—, a group —B—N(R⁸)—, a group —B₀—O—, a group

a group —CO—, a group —CH(OH)—, a group

a group —N═CH—, a group

a lower alkenylene group, a group —NHCO—B₁—, a group —NHCO—B₂—(W)u-, a group —B₀—O—B_(19a)—, a group

a group

a group

a group —S—, a lower alkynylene group, a lower alkylene group, a group

or a group —CO—NH—B₁₈a-, wherein R⁸ represents a hydrogen atom, a lower alkyl group that may have a lower alkoxy group as a substituent, a lower alkanoyl group, a phenyl lower alkyl group, or a lower alkylsulfonyl group, B represents a group —CO— or a lower alkylene group, B₀ represents a lower alkylene group, each of R^(9a) and R^(9b), which are identical or different, represents a hydrogen atom or a lower alkyl group R^(10a) represents a hydrogen atom or a lower alkyl group, B_(22a) represents a lower alkylene group or a lower alkenylene group, e represents 0 or 1, B₁ represents a lower alkenylene group that may have a phenyl group as a substituent, B₂ represents a lower alkylene group that may be substituted by a group selected from the group consisting of a lower alkoxy group and a phenyl group, W represents an oxygen atom, a group —NH—, or a sulfur atom, u represents 0 or 1, B_(18a) represents a lower alkylene group, B_(19a) represents a lower alkylene group, B_(20a) represents a lower alkylene group, B_(21a) represents a lower alkylene group, R^(8d) represents a hydrogen atom or a lower alkyl group, k represents 2 or 3, c represents 0 or 1, d′ represents 0 or 1, R^(10b) represents a hydrogen atom or a lower alkyl group, R⁶ represents a 5- to 15-membered monocyclic, dicyclic, or tricyclic saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein, the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of an oxo group; an optionally halogenated lower alkoxy group; an optionally halogenated lower alkyl group; a halogen atom; a lower alkylsulfonyl group; a phenyl group that may be substituted, on the phenyl ring, by an optionally halogenated lower alkyl group; a lower alkylthio group; a pyrrolyl group; a benzoyl group; a lower alkanoyl group; a lower alkoxycarbonyl group; and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent), an adamantyl group, a naphthyl group (wherein, the naphthalene ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a halogen atom, and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent), an alkyl group that may have a lower alkoxy group as a substituent, a cycloalkyl group that may be substituted, on the cycloalkyl ring, by a group selected from the group consisting of an amino-substituted lower alkyl group that may have a lower alkyl group on the amino group and a lower alkyl group that may have a halogen atom as a substituent, a lower alkenyl group that may have a halogen atom as a substituent, a lower alkanoyl group, a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group that may have a halogen atom as a substituent and a halogen atom, a group

a halogen atom-substituted lower alkyl group, or a cycloalkyl lower alkyl group, R⁷ represents a hydrogen atom, a phenyl group, a carboxy group, a hydroxyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a phenoxy group, a lower alkoxy group that may have a halogen atom as a substituent, a lower alkylenedioxy group, an amino group that may have, as a substituent, a group selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group, and a cycloalkyl group, a cyano group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkylsulfonyl group, an aminosulfonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein the heterocyclic ring may be substituted, by an oxo group), or a lower alkoxycarbonyl lower alkyl group, m represents an integer between 1 and 5, wherein when m represents 2 to 5, two to five R's may be identical or different, R² represents a hydrogen atom, a halogen atom, or a lower alkyl group, Y represents a group —O—, a group —N(R⁵)—, a group —CO—, a group —CH(OH)—, a lower alkylene group, a group —S(O)n-, or a group —C(═N—OH)—, R⁵ represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a phenyl lower alkyl group, or a cycloalkyl group, n represents 0, 1, or 2, A represents a group

or a group

p represents 1 or 2, R³ represents a hydrogen atom, a lower alkoxy group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a carboxy group, a group —CONR¹¹R¹², or a cyano group, wherein each of R¹¹ and R¹², which are identical or different, represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a phenyl group, or R¹¹ and R¹², together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, R⁴ represents an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group that may have an oxo group as a substituent on the pyrimidine ring, a 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group, a 1,2,4-oxadiazolyl lower alkyl group that may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a group

a group

or a group -(T)₁-N(R¹⁴) R¹⁵, R¹³ represents a hydrogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a benzoyl group, a morpholino-substituted lower alkanoyl group, a piperazinyl carbonyl lower alkyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a morpholinocarbonyl-substituted lower alkyl group, or an imidazolyl lower alkanoyl group, R^(13a) represents a hydrogen atom or a hydroxyl group, T represents a lower alkylene group, a group —N(R¹⁷)—B₃—CO—, a group —B₁₉—N(R¹⁸)—CO—, a group —B₄—CO—, a group -Q-B₅—CO—, a group —B₆—N(R¹⁸)—B₇—CO—, a group —CO—B₈—, a group —CH(OH)—B₉—, a group —CO—B₁₀—CO—, a group —CH(OH)—B₁₁—CO—, a group —CO—, a group —SO₂—, or a group —B_(23a)—CO—CO—, wherein R¹⁷ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylcarbonyl group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkenyl group, an amino-substituted lower alkanoyl group that may have a lower alkyl group as a substituent, or a lower alkylsulfonyl group, B₃ represents a lower alkylene group, B₁₉ represents a lower alkylene group, R¹⁸ represents a hydrogen atom or a lower alkyl group, B₄ represents a lower alkenylene group or a lower alkylene group that may have a hydroxyl group as a substituent, Q represents an oxygen atom or a group —S(O)n- (wherein n has the same meanings as described above), B₅ represents a lower alkylene group, B₆ represents a lower alkylene group, R¹⁹ represents a hydrogen atom or a lower alkanoyl group, B₇ represents a lower alkylene group, B₈ represents a lower alkylene group, B₉ represents a lower alkylene group, B₁₀ represents a lower alkylene group, B₁₁ represents a lower alkylene group, B_(23a) represents a lower alkylene group, l represents 0 or 1, R¹⁴ represents a hydrogen atom or an alkyl group that may have a hydroxyl group as a substituent, R¹⁵ represents (2) a hydroxyl group-substituted alkyl group, (3) a cycloalkyl group that may have a group selected from the group consisting of a hydroxyl group and a lower alkyl group as a substituent, (4) a phenoxy lower alkyl group, (5) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group; a lower alkoxy group that may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group that may have a lower alkyl group as a substituent; a hydroxyl group-substituted lower alkyl group; a phenyl lower alkyl group; a lower alkynyl group; an amino group that may have a lower alkylsulfonyl group as a substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; an anilino group that may have a halogen atom as a substituent on the phenyl ring; a lower alkoxycarbonyl group; a piperazinyl group that may have a lower alkyl group as a substituent on the piperazine ring; a pyrrolidinyl group that may have an oxo group as a substituent on the pyrrolidine ring; a lower alkanoylamino group; a cyano group; and a phenoxy group, (6) a phenoxy group, (7) a phenyl lower alkyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkyl group, (8) a phenyl lower alkyl group that has a lower alkylenedioxy group as a substituent on the phenyl ring, (10) a lower alkoxycarbonyl-substituted lower alkyl group, (11) a carboxy-substituted lower alkyl group, (12) an amino group that may have a lower alkanoyl group as a substituent, (13) a 1,2,3,4-tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group as a substituent(s) on the tetrahydroquinoline ring, (14) a cycloalkyl lower alkyl group, (15) a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (16) a pyridyl lower alkyl group, (17) an amino group-substituted lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, (18) a lower alkoxy lower alkyl group, (19) an imidazolyl group, (20) an imidazolyl lower alkyl group, (21) a 1,2,3,4-tetrahydroisoquinolylcarbonyl-substituted lower alkyl group, (22) a piperidinylcarbonyl group that may have a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, and a furyl lower alkyl group as a substituent on the piperidine ring, (23) a thiazolidinyl lower alkanoyl group that may have an oxo group as a substituent on the thiazolidine ring, (24) a piperidinyl group that may be substituted, on the piperidine ring, by a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, a lower alkyl group, a benzoyl group, and a furyl lower alkyl group, (25) a carbonyl lower alkyl group substituted by a group

(26) a carbonyl lower alkyl group substituted by a group

(27) a group —CO—B₂₀—N(R³⁶)R³⁷, (26a) a pyrrolidinyl lower alkyl group, (27a) a morpholino lower alkyl group, (28a) a phenyl lower alkenyl group, (29a) an anilinocarbonyl lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, (30a) an indolyl group, (31a) a piperazinyl lower alkyl group that may have, as a substituent on the piperazine ring, a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (32a) an amidino lower alkyl group that may have a lower alkyl group as a substituent, (33a) a fluorenyl group, (34a) a carbazolyl group that may have a lower alkyl group as a substituent on the carbazole ring, (35a) an amidino group that may have a lower alkyl group as a substituent, (36a) a piperazinyl-substituted oxalyl group that may have 1 to 3 groups selected from the group consisting of a phenyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group as a substituent(s) on the phenyl ring) and a pyridyl lower alkyl group as a substituent(s) on the piperazine ring, or (37a) a cyano-substituted lower alkyl group, R³⁴ represents an oxo group or a phenyl group, d represents an integer between 0 and 3, B₂₀ represents a lower alkylene group, R³⁶ and R³⁷, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring, R¹⁴ and R¹⁵, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring; or a group

wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of (28) a phenyl-substituted lower alkyl group, which has 1 to 2 phenyl groups and which may have a pyridyl group on the lower alkyl group, wherein the phenyl ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkanoyl group, an amino group that may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group, (29) a carbamoyl group, (30) a pyridyl lower alkyl group that may have, as a substituent(s) on the pyridine ring, 1 to 3 groups selected from the group consisting of a hydroxyl group and a lower alkyl group that may have a hydroxyl group as a substituent, (31) a pyrrolyl lower alkyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrrole ring, (32) a benzoxazolyl lower alkyl group, (33) a benzothiazolyl lower alkyl group, (34) a furyl lower alkyl group, (35) a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, an amino group that may have a lower alkylsulfonyl group as a substituent, a halogen atom, a lower alkoxy group, a lower alkyl group that may have a halogen atom as a substituent, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a thiazolidinylidene lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, and a lower alkylenedioxy group, (36) a pyrimidinyl group, (37) a pyrazinyl group, (38) a pyridyl group, (39) a lower alkoxycarbonyl group, (40) a thiazolidinyl lower alkanoyl group that may be substituted, on the thiazolidine ring, by a group selected from the group consisting of an oxo group and a group

(wherein each of R^(a) and R^(b) represents a lower alkyl group), (41) a lower alkyl group that may have a group selected from the group consisting of a hydroxyl group and a halogen atom as a substituent, (42) a lower alkanoyl group that may have a halogen atom as a substituent, (43) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a carbamoyl group that may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group, a lower alkoxycarbonyl group, a carboxy group, a cyano group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a benzoyl group that may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group that may have a halogen atom as a substituent on the phenyl ring, and a hydroxyl group, (44) a phenyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (45) a naphthyl lower alkyl group, (46) a phenoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (47) a phenoxy lower alkyl group, (48) a phenyl lower alkoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (49) a group —(B₁₂CO)t-N(R²⁰)R²¹, (50) a group —(CO)o-B₁₃—N(R²²)R²³, (51) a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may be substituted, on the 1,2,3,4-tetrahydronaphthalene ring, by 1 to 5 lower alkyl groups as a substituent(s), (52) a cycloalkyl group that may have a hydroxyl group as a substituent, (53) a piperidinyl group that may be substituted, on the piperidine ring, by 1 to 3 lower alkyl groups as a substituent(s), (54) a quinolyl lower alkyl group, (55) a 1,2,3,4-tetrazolyl lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent on the tetrazole ring, (56) a thiazolyl lower alkyl group that may have a phenyl group as a substituent on the thiazole ring, (57) a benzoyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent(s) on the phenyl ring, (58) a piperidinyl lower alkyl group that may have a lower alkyl group as a substituent on the piperidine ring, (59) an imidazolyl group that may have 1 to 3 phenyl groups as a substituent(s) on the imidazole ring, (60) a benzimidazolyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the benzimidazole ring, (61) a pyridyl lower alkoxy group, (62) a 1,2,3,4-tetrahydroquinolyl lower alkyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (63) a 1,3,4-oxadiazolyl lower alkyl group that may have an oxo group as a substituent on the 1,3,4-oxadiazole ring, (64) a cycloalkyl lower alkyl group, (65) a tetrahydropyranyl group, (66) a thienyl lower alkyl group, (67) a pyrimidinylcarbonyl group that may have an oxo group as a substituent on the pyrimidine ring, (68) a hydroxyl group, (69) a carboxy group, (70) a lower alkoxy lower alkyl group, (71) a lower alkoxy lower alkoxy group, (72) a benzoyloxy group, (73) a lower alkoxycarbonyl lower alkoxy group, (74) a carboxy lower alkoxy group, (75) a phenoxy lower alkanoyl group, (76) a 1,2,3,4-tetrahydroquinolylcarbonyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (77) a phenylsulfonyl group, (78) an imidazolyl lower alkanoyl group, (79) an imidazolyl lower alkyl group, (80) a pyridylcarbonyl group, (81) an imidazolylcarbonyl group, (82) a lower alkoxycarbonyl lower alkyl group, (83) a carboxy lower alkyl group, (84) a group —(O—B₁₅)s-CO—N(R²⁶)R²⁷, (85) a group —N(R²⁸)—CO—B₁₆—N(R²⁹)R³⁰, (86) a group —N(R³¹)—B₁₇—CO—N(R³²)R³³, (87) a benzoxazolyl group, (88a) a benzothienyl group, (89a) an oxo group, and (90a) a 1,2,3,4-tetrahydroquinolyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, B₁₂ represents a lower alkylene group, t represents 0 or 1, each of R²⁰ and R²¹, which are identical or different, represents a hydrogen atom; a cycloalkyl group; an amino group that may have a lower alkoxycarbonyl group as a substituent; a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring; a lower alkyl group; a lower alkyl group having 1 to 2 phenyl groups that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkylthio group; a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxy group that may have a halogen atom as a substituent and a lower alkyl group that may have a halogen atom as a substituent; a lower alkoxycarbonyl group; a cycloalkyl lower alkyl group; a pyrrolidinyl lower alkyl group that may have 1 to 3 lower alkyl groups that may have a hydroxyl group as a substituent on the pyrrolidine ring; an amino-substituted lower alkyl group that may have a group selected from the group consisting of a phenyl group and a lower alkyl group as a substituent; a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may have 1 to 5 lower alkyl groups as a substituent(s) on the 1,2,3,4-tetrahydronaphthalene ring; a naphthyl lower alkyl group; a pyridyl lower alkyl group; a quinolyl lower alkyl group; a 1,2,3,4-tetrazolyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent(s) on the tetrazole ring; a 1,2,4-triazolyl lower alkyl group; a tetrahydrofuryl lower alkyl group that may have a hydroxyl group as a substituent on the lower alkyl group; a phenoxy lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a nitro group as a substituent(s) on the phenyl ring; a phenyl lower alkanoyl group; a lower alkanoyl group that may have a halogen atom as a substituent; an imidazolyl lower alkanoyl group; a lower alkoxycarbonyl lower alkyl group; a pyridyl group; or a carboxy lower alkyl group, or R²⁰ and R²¹, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group that may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkyl group that may have a halogen atom as a substituent(s) on the phenyl ring, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, o represents 0 or 1, B₁₃ represents a lower alkylene group, each of R²² and R²³, which are identical or different, represents a hydrogen atom, a lower alkyl group, a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring, a phenoxy lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group, or a phenyl group, or R²² and R²³, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, B₁₅ represents a lower alkylene group, s represents 0 or 1, each of R²⁶ and R²⁷, which are identical or different, represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or an imidazolyl lower alkyl group, or R²⁶ and R²⁷, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring, as a substituent(s), R²⁸ represents a hydrogen atom or a lower alkyl group, B₁₆ represents a lower alkylene group, R²⁹ and R³⁰, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, R³¹ represents a hydrogen atom or a lower alkyl group, B₁₇ represents a lower alkylene group, R³² and R³³, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, provided that the above described aromatic compound or a salt thereof satisfy the following requirements (i) to (v): (i) when X₁ represents a group —CH═, then R³ represents a hydrogen atom; (ii) when X₁ represents a group —CH═, l represents 1, T represents —CO—, and R¹⁴ represents a hydrogen atom or an alkyl group that may have a hydroxyl group as a substituent, then R¹⁵ represents the group (24) described above; (iii) when X₁ represents a group —CH═, l represents 1, and T represents —N(R¹⁷)—B₃—CO—, then R¹⁴ and R¹⁶, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring, wherein the heterocyclic ring is substituted by 1 to 3 groups of (28) described above; (iv) when X₁ represents a nitrogen atom, and l represents 0, or when X₁ represents a nitrogen atom, l represents 1, and T represents —CO— or —SO₂, then R¹⁵ is not the group being any one of (5), (7), (19), and (20) described above; and (v) when R⁶ represents a cycloalkyl group wherein the cycloalkyl ring may be substituted by a group selected from the group consisting of an amino-substituted lower alkyl group that may have a lower alkyl group and a lower alkyl group that may have a halogen atom as a substituent, then R¹⁴ represents a group -(T)₁-N(R¹⁴)R¹⁶ (wherein T and l have the same meanings as described above, and R¹⁴ and R¹⁵, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated heterocyclic ring; or R¹⁴ and R¹⁵ form a group

which is characterized in that the compound is produced by the method described in any one of reaction formulas-1 to 46, 48, 49, 52, 59, 104, 105, 108 to 132, and
 135. 2. A pharmaceutical composition for treating fibrosis, characterized by comprising an aromatic compound represented by the following general formula (1A) or a salt thereof:

[wherein X₁ represents a nitrogen atom or a group —CH═, R¹ represents a group —Z—R⁶, Z represents a group —N(R⁸)—B—, a group —B—N(R⁸)—, a group —B₀—O—, a group

a group —CO—, a group —CH(OH)—, a group

a group —N═CH—, a group

a lower alkenylene group, a group —NHCO—B₁—, a group —NHCO—B₂—(W)u-, a group —B₀—O—B_(19a)—, a group

a group

a group

a group —S—, a lower alkynylene group, a lower alkylene group, a group

or a group —CO—NH—B₁₈a-, wherein R⁸ represents a hydrogen atom, a lower alkyl group that may have a lower alkoxy group as a substituent, a lower alkanoyl group, a phenyl lower alkyl group, or a lower alkylsulfonyl group, B represents a group —CO— or a lower alkylene group, B₀ represents a lower alkylene group, each of R^(9a) and R^(9b), which are identical or different, represents a hydrogen atom or a lower alkyl group R^(10a) represents a hydrogen atom or a lower alkyl group, B_(22a) represents a lower alkylene group or a lower alkenylene group, e represents 0 or 1, B₁ represents a lower alkenylene group that may have a phenyl group as a substituent, B₂ represents a lower alkylene group that may be substituted by a group selected from the group consisting of a lower alkoxy group and a phenyl group, W represents an oxygen atom, a group —NH—, or a sulfur atom, u represents 0 or 1, B_(18a) represents a lower alkylene group, B_(19a) represents a lower alkylene group, B_(20a) represents a lower alkylene group, B_(21a) represents a lower alkylene group, R^(8d) represents a hydrogen atom or a lower alkyl group, k represents 2 or 3, c represents 0 or 1, d′ represents 0 or 1, R^(10b) represents a hydrogen atom or a lower alkyl group, R⁶ represents a 5- to 15-membered monocyclic, dicyclic, or tricyclic saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein, the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of an oxo group; an optionally halogenated lower alkoxy group; an optionally halogenated lower alkyl group; a halogen atom; a lower alkylsulfonyl group; a phenyl group that may be substituted, on the phenyl ring, by an optionally halogenated lower alkyl group; a lower alkylthio group; a pyrrolyl group; a benzoyl group; a lower alkanoyl group; a lower alkoxycarbonyl group; and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent), an adamantyl group, a naphthyl group (wherein, the naphthalene ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a halogen atom, and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent), an alkyl group that may have a lower alkoxy group as a substituent, a cycloalkyl group that may be substituted, on the cycloalkyl ring, by a group selected from the group consisting of an amino-substituted lower alkyl group that may have a lower alkyl group on the amino group and a lower alkyl group that may have a halogen atom as a substituent, a lower alkenyl group that may have a halogen atom as a substituent, a lower alkanoyl group, a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group that may have a halogen atom as a substituent and a halogen atom, a group

a halogen atom-substituted lower alkyl group, or a cycloalkyl lower alkyl group, R⁷ represents a hydrogen atom, a phenyl group, a carboxy group, a hydroxyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a phenoxy group, a lower alkoxy group that may have a halogen atom as a substituent, a lower alkylenedioxy group, an amino group that may have, as a substituent, a group selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group, and a cycloalkyl group, a cyano group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkylsulfonyl group, an aminosulfonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein the heterocyclic ring may be substituted, by an oxo group), or a lower alkoxycarbonyl lower alkyl group, m represents an integer between 1 and 5, wherein when m represents 2 to 5, two to five R^(7s) may be identical or different, R² represents a hydrogen atom, a halogen atom, or a lower alkyl group, Y represents a group —O—, a group —N(R⁵)—, a group —CO—, a group —CH(OH)—, a lower alkylene group, a group —S(O)n-, or a group —C(═N—OH)—, R⁵ represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a phenyl lower alkyl group, or a cycloalkyl group, n represents 0, 1, or 2, A represents a group

or a group

p represents 1 or 2, R³ represents a hydrogen atom, a lower alkoxy group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a carboxy group, a group —CONR¹¹R¹², or a cyano group, wherein each of R¹¹ and R¹², which are identical or different, represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a phenyl group, or R¹¹ and R¹², together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, R⁴ represents an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group that may have an oxo group as a substituent on the pyrimidine ring, a 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group, a 1,2,4-oxadiazolyl lower alkyl group that may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a group

a group

or a group -(T)₁-N(R¹⁴)R¹⁵, R¹³ represents a hydrogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a benzoyl group, a morpholino-substituted lower alkanoyl group, a piperazinyl carbonyl lower alkyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a morpholinocarbonyl-substituted lower alkyl group, or an imidazolyl lower alkanoyl group, R^(13a) represents a hydrogen atom or a hydroxyl group, T represents a lower alkylene group, a group —N(R¹⁷)—B₃—CO—, a group —(B₁₉)_(e)—N(R¹⁸)—CO—, a group —B₄—CO—, a group -Q-B₅—CO—, a group —B₈—N(R¹⁹)—B₇—CO—, a group —CO—B₈—, a group —CH(OH)—B₉—, a group —CO—B₁₀—CO—, a group —CH(OH)—B₁₁—CO—, a group —CO—, a group —SO₂—, or a group —B_(23a)—CO—CO—, wherein R¹⁷ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylcarbonyl group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkenyl group, an amino-substituted lower alkanoyl group that may have a lower alkyl group as a substituent, or a lower alkylsulfonyl group, B₃ represents a lower alkylene group, B₁₉ represents a lower alkylene group, e represents 0 or 1, R¹⁸ represents a hydrogen atom or a lower alkyl group, B₄ represents a lower alkenylene group or a lower alkylene group that may have a hydroxyl group as a substituent, Q represents an oxygen atom or a group —S(O)n- (wherein n has the same meanings as described above), B₅ represents a lower alkylene group, B₆ represents a lower alkylene group, R¹⁹ represents a hydrogen atom or a lower alkanoyl group, B₇ represents a lower alkylene group, B₈ represents a lower alkylene group, B₉ represents a lower alkylene group, B₁₀ represents a lower alkylene group, B₁₁ represents a lower alkylene group, B_(23a) represents a lower alkylene group, l represents 0 or 1, each of R¹⁴ and R¹⁵, which are identical or different represents (1) a hydrogen atom, (2) an alkyl group that may have a hydroxyl group as a substituent, (3) a cycloalkyl group that may have a group selected from the group consisting of a hydroxyl group and a lower alkyl group as a substituent, (4) a phenoxy lower alkyl group, (5) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group; a lower alkoxy group that may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group that may have a lower alkyl group as a substituent; a hydroxyl group-substituted lower alkyl group; a phenyl lower alkyl group; a lower alkynyl group; an amino group that may have a lower alkylsulfonyl group as a substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; an anilino group that may have a halogen atom as a substituent on the phenyl ring; a lower alkoxycarbonyl group; a piperazinyl group that may have a lower alkyl group as a substituent on the piperazine ring; a pyrrolidinyl group that may have an oxo group as a substituent on the pyrrolidine ring; a lower alkanoylamino group; a cyano group; and a phenoxy group, (6) a phenoxy group, (7) a phenyl lower alkyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkyl group, (8) a phenyl lower alkyl group that has a lower alkylenedioxy group as a substituent on the phenyl ring, (9) a lower alkanoyl group, (10) a lower alkoxycarbonyl-substituted lower alkyl group, (11) a carboxy-substituted lower alkyl group, (12) an amino group that may have a lower alkanoyl group as a substituent, (13) a 1,2,3,4-tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group as a substituent(s) on the tetrahydroquinoline ring, (14) a cycloalkyl lower alkyl group, (15) a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (16) a pyridyl lower alkyl group, (17) an amino group-substituted lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, (18) a lower alkoxy lower alkyl group, (19) an imidazolyl group, (20) an imidazolyl lower alkyl group, (21) a 1,2,3,4-tetrahydroisoquinolylcarbonyl-substituted lower alkyl group, (22) a piperidinylcarbonyl group that may have a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, and a furyl lower alkyl group as a substituent on the piperidine ring, (23) a thiazolidinyl lower alkanoyl group that may have an oxo group as a substituent on the thiazolidine ring, (24) a piperidinyl group that may be substituted, on the piperidine ring, by a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, a lower alkyl group, a benzoyl group, and a furyl lower alkyl group, (25) a carbonyl lower alkyl group substituted by a group

(26) a carbonyl lower alkyl group substituted by a group

(27) a group —CO—B₂₀—N(R³⁶)R³⁷, (26a) a pyrrolidinyl lower alkyl group, (27a) a morpholino lower alkyl group, (28a) a phenyl lower alkenyl group, (29a) an anilinocarbonyl lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, (30a) an indolyl group, (31a) a piperazinyl lower alkyl group that may have, as a substituent on the piperazine ring, a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (32a) an amidino lower alkyl group that may have a lower alkyl group as a substituent, (33a) a fluorenyl group, (34a) a carbazolyl group that may have a lower alkyl group as a substituent on the carbazole ring, (35a) an amidino group that may have a lower alkyl group as a substituent, (36a) a piperazinyl-substituted oxalyl group that may have 1 to 3 groups selected from the group consisting of a phenyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group as a substituent(s) on the phenyl ring) and a pyridyl lower alkyl group as a substituent(s) on the piperazine ring, or (37a) a cyano-substituted lower alkyl group, R³⁴ represents an oxo group or a phenyl group, d represents an integer between 0 and 3, B₂₀ represents a lower alkylene group, R³⁶ and R³⁷, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring, R¹⁴ and R¹⁵, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring; or a group

wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of (28) a phenyl-substituted lower alkyl group, which has 1 to 2 phenyl groups and which may have a pyridyl group on the lower alkyl group, wherein the phenyl ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkanoyl group, an amino group that may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group, (29) a carbamoyl group, (30) a pyridyl lower alkyl group that may have, as a substituent(s) on the pyridine ring, 1 to 3 groups selected from the group consisting of a hydroxyl group and a lower alkyl group that may have a hydroxyl group as a substituent, (31) a pyrrolyl lower alkyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrrole ring, (32) benzoxazolyl lower alkyl group, (33) a benzothiazolyl lower alkyl group, (34) a furyl lower alkyl group, (35) a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, an amino group that may have a lower alkylsulfonyl group as a substituent, a halogen atom, a lower alkoxy group, a lower alkyl group that may have a halogen atom as a substituent, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a thiazolidinylidene lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, and a lower alkylenedioxy group, (36) a pyrimidinyl group, (37) a pyrazinyl group, (38) a pyridyl group, (39) a lower alkoxycarbonyl group, (40) a thiazolidinyl lower alkanoyl group that may be substituted, on the thiazolidine ring, by a group selected from the group consisting of an oxo group and a group

(wherein each of R^(a) and R^(b) represents a lower alkyl group), (41) a lower alkyl group that may have a group selected from the group consisting of a hydroxyl group and a halogen atom as a substituent, (42) a lower alkanoyl group that may have a halogen atom as a substituent, (43) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a carbamoyl group that may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group, a lower alkoxycarbonyl group, a carboxy group, a cyano group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a benzoyl group that may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group that may have a halogen atom as a substituent on the phenyl ring, and a hydroxyl group, (44) a phenyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (45) a naphthyl lower alkyl group, (46) a phenoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (47) a phenoxy lower alkyl group, (48) a phenyl lower alkoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (49) a group —(B₁₂CO)t-N(R²⁰)R²¹, (50) a group —(CO)o-B₁₃—N(R²²)R²³, (51) a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may be substituted, on the 1,2,3,4-tetrahydronaphthalene ring, by 1 to 5 lower alkyl groups as a substituent(s), (52) a cycloalkyl group that may have a hydroxyl group as a substituent, (53) a piperidinyl group that may be substituted, on the piperidine ring, by 1 to 3 lower alkyl groups as a substituent(s), (54) a quinolyl lower alkyl group, (55) a 1,2,3,4-tetrazolyl lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent on the tetrazole ring, (56) a thiazolyl lower alkyl group that may have a phenyl group as a substituent on the thiazole ring, (57) a benzoyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent(s) on the phenyl ring, (58) a piperidinyl lower alkyl group that may have a lower alkyl group as a substituent on the piperidine ring, (59) an imidazolyl group that may have 1 to 3 phenyl groups as a substituent(s) on the imidazole ring, (60) a benzimidazolyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the benzimidazole ring, (61) a pyridyl lower alkoxy group, (62) a 1,2,3,4-tetrahydroquinolyl lower alkyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (63) a 1,3,4-oxadiazolyl lower alkyl group that may have an oxo group as a substituent on the 1,3,4-oxadiazole ring, (64) a cycloalkyl lower alkyl group, (65) a tetrahydropyranyl group, (66) a thienyl lower alkyl group, (67) a pyrimidinylcarbonyl group that may have an oxo group as a substituent on the pyrimidine ring, (68) a hydroxyl group, (69) a carboxy group, (70) a lower alkoxy lower alkyl group, (71) a lower alkoxy lower alkoxy group, (72) a benzoyloxy group, (73) a lower alkoxycarbonyl lower alkoxy group, (74) a carboxy lower alkoxy group, (75) a phenoxy lower alkanoyl group, (76) a 1,2,3,4-tetrahydroquinolylcarbonyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (77) a phenylsulfonyl group, (78) an imidazolyl lower alkanoyl group, (79) an imidazolyl lower alkyl group, (80) a pyridylcarbonyl group, (81) an imidazolylcarbonyl group, (82) a lower alkoxycarbonyl lower alkyl group, (83) a carboxy lower alkyl group, (84) a group —(O—B₁₅)s-CO—N(R²⁶) R²⁷, (85) a group —N(R²⁸)—CO—B₁₆—N(R²⁹)R³⁰, (86) a group —N(R³¹)—B₁₇—CO—N(R³²) R³³, (87) a benzoxazolyl group, (88a) a benzothienyl group, (89a) an oxo group, and (90a) a 1,2,3,4-tetrahydroquinolyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, B₁₂ represents a lower alkylene group, t represents 0 or 1, each of R²⁰ and R²¹, which are identical or different, represents a hydrogen atom; a cycloalkyl group; an amino group that may have a lower alkoxycarbonyl group as a substituent; a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring; a lower alkyl group; a lower alkyl group having 1 to 2 phenyl groups that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkylthio group; a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxy group that may have a halogen atom as a substituent and a lower alkyl group that may have a halogen atom as a substituent; a lower alkoxycarbonyl group; a cycloalkyl lower alkyl group; a pyrrolidinyl lower alkyl group that may have 1 to 3 lower alkyl groups that may have a hydroxyl group as a substituent on the pyrrolidine ring; an amino-substituted lower alkyl group that may have a group selected from the group consisting of a phenyl group and a lower alkyl group as a substituent; a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may have 1 to 5 lower alkyl groups as a substituent(s) on the 1,2,3,4-tetrahydronaphthalene ring; a naphthyl lower alkyl group; a pyridyl lower alkyl group; a quinolyl lower alkyl group; a 1,2,3,4-tetrazolyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent(s) on the tetrazole ring; a 1,2,4-triazolyl lower alkyl group; a tetrahydrofuryl lower alkyl group that may have a hydroxyl group as a substituent on the lower alkyl group; a phenoxy lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a nitro group as a substituent(s) on the phenyl ring; a phenyl lower alkanoyl group; a lower alkanoyl group that may have a halogen atom as a substituent; an imidazolyl lower alkanoyl group; a lower alkoxycarbonyl lower alkyl group; a pyridyl group; or a carboxy lower alkyl group, or R²⁰ and R²¹, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group that may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkyl group that may have a halogen atom as a substituent(s) on the phenyl ring, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, o represents 0 or 1, B₁₃ represents a lower alkylene group, each of R²² and R²³, which are identical or different, represents a hydrogen atom, a lower alkyl group, a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring, a phenoxy lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group, or a phenyl group, or R²² and R²³, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, B₁₅ represents a lower alkylene group, s represents 0 or 1, each of R²⁶ and R²⁷, which are identical or different, represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or an imidazolyl lower alkyl group, or R²⁶ and R²⁷, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring, as a substituent(s), R²⁸ represents a hydrogen atom or a lower alkyl group, B₁₆ represents a lower alkylene group, R²⁹ and R³⁰, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, R³¹ represents a hydrogen atom or a lower alkyl group, B₁₇ represents a lower alkylene group, R³² and R³³, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring].
 3. The pharmaceutical composition for treating fibrosis according to claim 2, which is characterized in that it comprises the aromatic compound represented by general formula (1) or a salt thereof as defined in claim
 1. 4. The pharmaceutical composition for treating fibrosis according to claim 2, which comprises an aromatic compound selected from the group consisting of: N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide, N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperazin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-{6-[(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]pyridin-3-yl}-4-trifluoromethylbenzamide, N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide, N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-3,4-dichlorobenzamide, N-[6-({4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenyl}methylamino)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, 1-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3-(3,4-dichlorophenyl)-1-ethylurea, N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide, N-[6-(4-{[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide, N-(6-{4-[3-(4-piperonylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide, N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, N-{6-[(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]pyridin-3-yl}-4-trifluoromethylbenzamide, N-(6-{4-[(2-{4-[4-(4-fluorobenzoyl)phenyl]-piperazin-1-yl}-2-oxoethyl)methylamino]-2-methoxyphenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide, 2-(4-piperonylpiperazin-1-yl)-N-{3-methyl-4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenyl}-2-oxoacetamide, N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-2-fluoro-4-trifluoromethylbenzamide, N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, and 4-(3-{3-methyl-4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]phenyl}-2-oxohexahydropyrimidin-1-yl)benzoic acid ethyl ester, or salts thereof.
 5. The pharmaceutical composition for treating fibrosis according to claim 2, wherein the fibrosis is lung fibrosis.
 6. The pharmaceutical composition for treating fibrosis according to claim 2, wherein the fibrosis is hepatic fibrosis.
 7. The pharmaceutical composition for treating fibrosis according to claim 2, wherein the fibrosis is glomerulosclerosis. 